Proton pump inhibitors

ABSTRACT

A proton pump inhibitor containing a compound represented by the formula (I) 
     
       
         
         
             
             
         
       
     
     wherein X and Y are the same or different and each is a bond or a spacer having 1 to 20 carbon atoms in the main chain, R 1  is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R 2 , R 3  and R 4  are the same or different and each is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted thienyl group, an optionally substituted benzo[b]thienyl group, an optionally substituted furyl group, an optionally substituted pyridyl group, an optionally substituted pyrazolyl group, an optionally substituted pyrimidinyl group, an acyl group, a halogen atom, a cyano group or a nitro group, R 5  and R 6  are the same or different and each is a hydrogen atom or an optionally substituted hydrocarbon group, which has a superior proton pump action and shows an antiulcer activity and the like after conversion to a proton pump inhibitor in the body, or a salt thereof. or a prodrug thereof is provided.

TECHNICAL FIELD

The present invention relates to pyrrole compounds having a proton pumpinhibitory activity.

BACKGROUND ART

Proton pump inhibitors represented by omeprazole, which suppresssecretion of gastric acid for the treatment of peptic ulcer, refluxesophagitis and the like, have been widely used in clinical situations.However, the existing proton pump inhibitors are associated withproblems in terms of effect and side effects. To be specific, since theexisting proton pump inhibitors are unstable under acidic conditions,they are often formulated as enteric preparations, in which case severalhours are required before expression of the effect. In addition, sincethe existing proton pump inhibitors show inconsistent treatment effectsdue to metabolic enzyme polymorphism and drug interaction withpharmaceutical agents such as diazepam and the like, an improvement hasbeen desired.

As pyrrole compounds having a proton pump inhibitory action,EP-A-0259085 describes a compound represented by the formula:

and the like.

As a production intermediate for a compound having a CCK antagonisticaction, WO92/04025 describes a compound represented by the formula:

As compounds having a thromboxane A2 (TXA2) antagonistic action and aTXA2 synthase inhibitory action, JP-A-8-119936 describes a compoundrepresented by the formula:

wherein r1 is carboxy, protected carboxy, carboxy(lower)alkyl, protectedcarboxy(lower)alkyl, carboxy(lower)alkenyl or protectedcarboxy(lower)alkenyl, r2 is hydrogen; lower alkyl; heterocyclic(lower)alkyl optionally having aminoimino or protected aminoimino;heterocyclic (lower)alkenyl; or heterocyclic carbonyl, r3 is hydrogen orlower alkyl, r4 is acyl, r5 is hydrogen, A₀ is lower alkylene, and Z₀ isS or NH, provided when r1 is carboxy or protected carboxy, then Z₀ isNH.

Moreover, as a therapeutic drug for neoplastic diseases or autoimmunediseases, WO2004/103968 describes a compound represented by the formula:

wherein r6 is aryl, aralkyl or heteroaryl, r7 is aryl or heteroaryl, andr8 is aryl, heteroaryl or an optionally substituted aminomethyl.

A pharmaceutical agent that effectively suppresses gastric acidsecretion as known proton pump inhibitors, which is improved ininstability under acidic conditions, dispersion of effects due tometabolic enzyme polymorphism and drug interaction, which are problemsof known proton pump inhibitors, is expected to show more superiortreatment effect on peptic ulcer, reflux esophagitis and the like. Asthe situation stands, however, a proton pump inhibitor capable ofsufficiently satisfying these requirements has not been found. It istherefore an object of the present invention to provide a compoundhaving a superior acid secretion suppressive effect (particularly, anacid secretion suppressive effect based on proton pump inhibition),which has been improved in these problems.

DISCLOSURE OF THE INVENTION

The present inventors have conducted various studies and found that acompound represented by the formula (I):

whereinX and Y are the same or different and each is a bond or a spacer having1 to 20 atoms in the main chain,R¹ is an optionally substituted hydrocarbon group or an optionallysubstituted heterocyclic group,R², R³ and R⁴ are the same or different and each is a hydrogen atom, anoptionally substituted hydrocarbon group, an optionally substitutedthienyl group, an optionally substituted benzo[b]thienyl group, anoptionally substituted furyl group, an optionally substituted pyridylgroup, an optionally substituted pyrazolyl group, an optionallysubstituted pyrimidinyl group, an acyl group, a halogen atom, a cyanogroup or a nitro group, andR⁵ and R⁶ are the same or different and each is a hydrogen atom or anoptionally substituted hydrocarbon group,or a salt thereof [hereinafter to be abbreviated as compound (I)]unexpectedly has a very strong proton pump inhibitory effect, and isfully satisfactory as a pharmaceutical agent, which resulted in thecompletion of the present invention.

Accordingly, the present invention relates to the following.

[1] A proton pump inhibitor comprising a compound represented by theformula (I)

whereinX and Y are the same or different and each is a bond or a spacer having1 to 20 atoms in the main chain,R¹ is an optionally substituted hydrocarbon group or an optionallysubstituted heterocyclic group,R², R³ and R⁴ are the same or different and each is a hydrogen atom, anoptionally substituted hydrocarbon group, an optionally substitutedthienyl group, an optionally substituted benzo[b]thienyl group, anoptionally substituted furyl group, an optionally substituted pyridylgroup, an optionally substituted pyrazolyl group, an optionallysubstituted pyrimidinyl group, an acyl group, a halogen atom, a cyanogroup or a nitro group, andR⁵ and R⁶ are the same or different and each is a hydrogen atom or anoptionally substituted hydrocarbon group,or a salt thereof, or a prodrug thereof,[2] the inhibitor of the above-mentioned [1], wherein X is —SO₂—,—SO₂—N(R⁷)— (wherein R⁷ is a hydrogen atom or an optionally substitutedhydrocarbon group), —N(R⁸)—SO₂— (wherein R⁸ is a hydrogen atom or anoptionally substituted hydrocarbon group), —N(R⁹)— (wherein R⁹ is ahydrogen atom or an optionally substituted hydrocarbon group) or —O—,[3] the inhibitor of the above-mentioned [1], wherein X is —SO₂—,[4] an agent for the prophylaxis or treatment of peptic ulcer,Zollinger-Ellison syndrome, gastritis, reflux esophagitis,gastroesophageal reflux disease (Symptomatic Gastroesophageal RefluxDisease (symptomatic GERD)) free of esophagitis, NUD (Non UlcerDyspepsia), gastric cancer, stomach MALT lymphoma, ulcer caused by anon-steroidal anti-inflammatory agent or gastric hyperacidity and ulcerdue to postoperative stress; an inhibitor of upper gastrointestinalhemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagicgastritis or invasive stress, which comprises the proton pump inhibitorof the above-mentioned [1],[5] a compound represented by the formula (II-a)

whereinX¹ is —SO₂—, —SO₂—N(R⁷)— (wherein R⁷ is a hydrogen atom or an optionallysubstituted hydrocarbon group), —N(R⁸)—SO₂— (wherein R⁸ is a hydrogenatom or an optionally substituted hydrocarbon group), —N(R⁹)— (whereinR⁹ is a hydrogen atom or an optionally substituted hydrocarbon group) or—O—,Y¹ is an optionally substituted alkylene group, R¹⁰ is an optionallysubstituted hydrocarbon group or an optionally substituted heterocyclicgroup,R¹¹ is a hydrogen atom, an optionally substituted hydrocarbon group, anoptionally substituted thienyl group, an optionally substitutedbenzo[b]thienyl group, an optionally substituted furyl group, anoptionally substituted pyridyl group, an optionally substitutedpyrazolyl group or an optionally substituted pyrimidinyl group,R¹² and R¹³ are each independently a hydrogen atom, an optionallysubstituted hydrocarbon group, an acyl group, a halogen atom, a cyanogroup or a nitro group (provided that R¹² and R¹³ are not simultaneouslyhydrogen atoms), and R¹⁴ and R¹⁵ are each independently a hydrogen atomor an optionally substituted hydrocarbon group,with the proviso that3-[[2,3-dimethyl-1-(4-methylphenyl)sulfonyl]-1H-pyrrol-4-yl]-2-methyl-alaninemethyl ester is excluded,or a salt thereof,[6] a compound represented by the formula (II-b)

whereinX² is a —SO₂—N(R⁷)— (wherein R⁷ is a hydrogen atom or an optionallysubstituted hydrocarbon group), —N(R⁸)—SO₂— (wherein R⁸ is a hydrogenatom or an optionally substituted hydrocarbon group), —N(R⁹)— (whereinR⁹ is a hydrogen atom or an optionally substituted hydrocarbon group) or—O—,Y² is an optionally substituted alkylene group,R¹⁶ is an optionally substituted hydrocarbon group or an optionallysubstituted heterocyclic group,R¹⁷ is a hydrogen atom, an optionally substituted hydrocarbon group, anoptionally substituted thienyl group, an optionally substitutedbenzo[b]thienyl group, an optionally substituted furyl group, anoptionally substituted pyridyl group, an optionally substitutedpyrazolyl group or an optionally substituted pyrimidinyl group,R¹⁸ and R¹⁹ are each a hydrogen atom, andR²⁰ and R²¹ are each independently a hydrogen atom or an optionallysubstituted hydrocarbon group,provided that R¹⁷ should not be a 1,3-dioxaindan-6-yl group,or a salt thereof,[7] a compound represented by the formula (II-c)

wherein

X³ is a —SO₂—,

Y³ is a methylene group (—CH₂—),R²² is an alkyl group, an optionally substituted phenyl group or anoptionally substituted thienyl group,R²³ is an optionally substituted C₆₋₁₄ aryl group, an optionallysubstituted thienyl group, an optionally substituted benzo[b]thienylgroup, an optionally substituted furyl group, an optionally substitutedpyridyl group, an optionally substituted pyrazolyl group or anoptionally substituted pyrimidinyl group,R²⁴ and R²⁵ are each a hydrogen atom,R²⁶ is a hydrogen atom or a methyl group, andR²⁷ is a methyl group,or a salt thereof,[8] a compound selected from

-   N-methyl-1-[1-(phenylsulfonyl)-5-(3-thienyl)-1H-pyrrol-3-yl]methanamine,-   N-methyl-1-[5-phenyl-1-(3-thienylsulfonyl)-1H-pyrrol-3-yl]methanamine,-   N-methyl-1-(1-{[3-(methylsulfonyl)phenyl]sulfonyl}-5-phenyl-1H-pyrrol-3-yl)methanamine,-   1-[1-(1-benzothien-2-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]-N-methylmethanamine,-   1-[5-(2-fluorophenyl)-1-{[3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine,-   1-{5-(2-fluorophenyl)-1-[(2-fluorophenyl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine    and-   N-methyl-3-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzamide,    or a salt thereof,    [9] a prodrug of the compound of any of the above-mentioned [5] to    [7],    [10] a pharmaceutical agent comprising the compound of any of the    above-mentioned [5] to [7] or a prodrug thereof,    [11] the pharmaceutical agent of the above-mentioned [10], which is    an agent for the prophylaxis or treatment of peptic ulcer,    Zollinger-Ellison syndrome, gastritis, reflux esophagitis,    gastroesophageal reflux disease (Symptomatic Gastroesophageal Reflux    Disease (symptomatic GERD)) free of esophagitis, NUD (Non Ulcer    Dyspepsia), gastric cancer, stomach MALT lymphoma, ulcer caused by a    non-steroidal anti-inflammatory agent or gastric hyperacidity and    ulcer due to postoperative stress; or an inhibitor of upper    gastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer,    hemorrhagic gastritis or invasive stress,    [12] a method for the prophylaxis or treatment of peptic ulcer,    Zollinger-Ellison syndrome, gastritis, reflux esophagitis,    gastroesophageal reflux disease (Symptomatic Gastroesophageal Reflux    Disease (symptomatic GERD)) free of esophagitis, NUD (Non Ulcer    Dyspepsia), gastric cancer, stomach MALT lymphoma, ulcer caused by a    non-steroidal anti-inflammatory agent or gastric hyperacidity and    ulcer due to postoperative stress; or a method of inhibiting upper    gastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer,    hemorrhagic gastritis or invasive stress, which comprises    administering an effective amount of the compound of any of the    above-mentioned [5] to [7] or a prodrug thereof to the mammal, and    [13] use of the compound of any of the above-mentioned [5] to [7] or    a prodrug thereof, for the production of an agent for the    prophylaxis or treatment of peptic ulcer, Zollinger-Ellison    syndrome, gastritis, reflux esophagitis, gastroesophageal reflux    disease (Symptomatic Gastroesophageal Reflux Disease (symptomatic    GERD)) free of esophagitis, NUD (Non Ulcer Dyspepsia), gastric    cancer, stomach MALT lymphoma, ulcer caused by a non-steroidal    anti-inflammatory agent or gastric hyperacidity and ulcer due to    postoperative stress an inhibitor of upper gastrointestinal    hemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagic    gastritis or invasive stress.

In another embodiment, the present invention relates to [13] a protonpump inhibitor comprising a compound represented by the formula (I⁰)

whereinX⁴ and Y⁴ are the same or different and each is a bond or a spacerhaving 1 to 20 atoms in the main chain,R²⁸ is an optionally substituted hydrocarbon group,R²⁹, R³⁰ and R³¹ are the same or different and each is a hydrogen atomor an optionally substituted hydrocarbon group, an acyl group, a halogenatom, a cyano group or a nitro group,R³² and R³³ are the same or different and each is a hydrogen atom or anoptionally substituted hydrocarbon group,or a salt thereof, or a prodrug thereof,[14] the inhibitor of the above-mentioned [13], wherein X⁴ is —SO₂—,—SO₂—N(R⁷)— (wherein R⁷ is a hydrogen atom or an optionally substitutedhydrocarbon group), —N(R⁸)—SO₂— (wherein R⁸ is a hydrogen atom or anoptionally substituted hydrocarbon group), —N(R⁹)— (wherein R⁹ is ahydrogen atom or an optionally substituted hydrocarbon group) or —O—,[15] the inhibitor of the above-mentioned [13], wherein X⁴ is —SO₂—,[16] an agent for the prophylaxis or treatment of peptic ulcer,Zollinger-Ellison syndrome, gastritis, reflux esophagitis,gastroesophageal reflux disease (Symptomatic Gastroesophageal RefluxDisease (symptomatic GERD)) free of esophagitis, NUD (Non UlcerDyspepsia), gastric cancer, stomach MALT lymphoma, ulcer caused by anon-steroidal anti-inflammatory agent or gastric hyperacidity and ulcerdue to postoperative stress; an inhibitor of upper gastrointestinalhemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagicgastritis or invasive stress, which comprises the proton pump inhibitorof the above-mentioned [13],[17] a compound represented by the formula (II)

whereinX⁵ is —SO₂—, —SO₂—N(R⁷)— (wherein R⁷ is a hydrogen atom or an optionallysubstituted hydrocarbon group), —N(R⁸)—SO₂— (wherein R⁸ is a hydrogenatom or an optionally substituted hydrocarbon group), —N(R⁹)— (whereinR⁹ is a hydrogen atom or an optionally substituted hydrocarbon group) or—O—,Y⁵ is an optionally substituted alkylene group,R³⁴ is an optionally substituted hydrocarbon group,R³⁵ is a hydrogen atom or an optionally substituted hydrocarbon group,R³⁶ and R³⁷ are each independently a hydrogen atom, an optionallysubstituted hydrocarbon group, an acyl group, a halogen atom, a cyanogroup or a nitro group,R³⁸ and R³⁹ are each independently a hydrogen atom or an optionallysubstituted hydrocarbon group,Provided that R³⁵ and/or R³⁷ should not be a 1,3-dioxaindan-6-yl group,with the proviso that3-[[2,3-dimethyl-1-(4-methylphenyl)sulfonyl]-1H-pyrrol-4-yl]-2-methyl-alaninemethyl ester is excluded,or a salt thereof,[18] the compound of the above-mentioned [17], wherein X⁵ is —SO₂—,[19] a prodrug of the compound of the above-mentioned [17],[20] a pharmaceutical agent comprising the compound of theabove-mentioned [17] or a prodrug thereof,[21] the pharmaceutical agent of the above-mentioned [20], which is anagent for the prophylaxis or treatment of peptic ulcer,Zollinger-Ellison syndrome, gastritis, reflux esophagitis,gastroesophageal reflux disease (Symptomatic Gastroesophageal RefluxDisease (symptomatic GERD)) free of esophagitis, NUD (Non UlcerDyspepsia), gastric cancer, stomach MALT lymphoma, ulcer caused by anon-steroidal anti-inflammatory agent or gastric hyperacidity and ulcerdue to postoperative stress; or an inhibitor of upper gastrointestinalhemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagicgastritis or invasive stress,[22] a method for the prophylaxis or treatment of peptic ulcer,Zollinger-Ellison syndrome, gastritis, reflux esophagitis,gastroesophageal reflux disease (Symptomatic Gastroesophageal RefluxDisease (symptomatic GERD)) free of esophagitis, NUD (Non UlcerDyspepsia), gastric cancer, stomach MALT lymphoma, ulcer caused by anon-steroidal anti-inflammatory agent or gastric hyperacidity and ulcerdue to postoperative stress; or a method of inhibiting uppergastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer,hemorrhagic gastritis or invasive stress, which comprises administeringan effective amount of the compound of any of the above-mentioned [17]or a prodrug thereof to the mammal, and[23] use of the compound of any of the above-mentioned [17] or a prodrugthereof, for the production of an agent for the prophylaxis or treatmentof peptic ulcer, Zollinger-Ellison syndrome, gastritis, refluxesophagitis, gastroesophageal reflux disease (SymptomaticGastroesophageal Reflux Disease (symptomatic GERD)) free of esophagitis,NUD (Non Ulcer Dyspepsia), gastric cancer, stomach MALT lymphoma, ulcercaused by a non-steroidal anti-inflammatory agent or gastrichyperacidity and ulcer due to postoperative stress; an inhibitor ofupper gastrointestinal hemorrhage due to peptic ulcer, acute stressulcer, hemorrhagic gastritis or invasive stress.

BEST MODE FOR EMBODYING THE INVENTION

In the formula (I), the “spacer having 1 to 20 atoms in the main chain”for X or Y means a divalent group having 1 to 20 contiguous atoms in themain chain. Here, the “atoms in the main chain” is counted such that thenumber of atoms in the main chain becomes minimum.

As the “spacer having 1 to 20 atoms in the main chain”, for example, adivalent group that can be formed with 1 to 5 (preferably 1 to 3)contiguous groups selected from

—O—; —S—; —CO—; —SO—; —SO₂—;

—NR⁴⁰— (wherein R⁴⁰ is a hydrogen atom, an optionally substitutedhydrocarbon group, an optionally substituted (e.g., halogenated) C₁₋₆alkyl-carbonyl, or an optionally substituted (e.g., halogenated) C₁₋₆alkylsulfonyl); anda divalent C₁₋₆ aliphatic hydrocarbon group optionally havingsubstituent(s)and the like can be mentioned.

As the “hydrocarbon group” of the “optionally substituted hydrocarbongroup” for R⁴⁰, for example, a chain or cyclic hydrocarbon group (e.g.,alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl etc.) can bementioned. Of these, a chain or cyclic hydrocarbon group having 1 to 16carbon atoms and the like are preferable.

As the “alkyl”, for example, C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.)and the like can be mentioned.

As the “alkenyl”, for example, C₂₋₆ alkenyl (e.g., vinyl, allyl,isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl,1-methyl-2-propenyl, 2-methyl-1-propenyl etc.) and the like can bementioned.

As the “alkynyl”, for example, C₂₋₆ alkynyl (e.g., ethynyl, propargyl,1-butynyl, 2-butynyl, 3-butynyl, 1-hexynyl etc.) and the like can bementioned.

As the “cycloalkyl”, for example, C₃₋₇ cycloalkyl (e.g., cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.) and the like canbe mentioned.

As the “aryl”, for example, C₆₋₁₄ aryl (e.g., phenyl, 1-naphthyl,2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl etc.)and the like can be mentioned.

As the “aralkyl”, for example, C₇₋₁₆ aralkyl (e.g., phenyl-C₁₋₆ alkyl,naphthyl-C₁₋₆ alkyl or diphenyl-C₁₋₄ alkyl etc. such as benzyl,phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl,2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl and thelike) and the like can be mentioned.

When the above-mentioned hydrocarbon group is an alkyl, an alkenyl or analkynyl, the hydrocarbon group is optionally substituted by 1 to 3substituents selected from (1) a halogen atom (e.g., a fluorine atom, achlorine atom, a bromine atom, an iodine atom etc.), (2) nitro, (3)cyano, (4) hydroxy, (5) C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy,fluoromethoxy etc.) optionally having 1 to 3 halogen atoms (e.g., afluorine atom, a chlorine atom, a bromine atom, an iodine atom), (6)C₆₋₁₄ aryloxy (e.g., phenyloxy, naphthyloxy etc.), (7) C₇₋₁₆ aralkyloxy(e.g., benzyloxy, phenethyloxy, diphenylmethyloxy, 1-naphthylmethyloxy,2-naphthylmethyloxy, 2,2-diphenylethyloxy, 3-phenylpropyloxy,4-phenylbutyloxy, 5-phenylpentyloxy etc.), (8) mercapto, (9) C₁₋₆alkylthio (e.g., methylthio, difluoromethylthio, trifluoromethylthio,ethylthio, propylthio, isopropylthio, butylthio,4,4,4-trifluorobutylthio, pentylthio, hexylthio etc.) optionally having1 to 3 halogen atoms (e.g., a fluorine atom, a chlorine atom, a bromineatom, an iodine atom), (10) C₆₋₁₄ arylthio (e.g., phenylthio,naphthylthio etc.), (11) C₇₋₁₆ aralkylthio (e.g., benzylthio,phenethylthio, diphenylmethylthio, 1-naphthylmethylthio,2-naphthylmethylthio, 2,2-diphenylethylthio, 3-phenylpropylthio,4-phenylbutylthio, 5-phenylpentylthio etc.), (12) amino, (13) mono-C₁₋₆alkylamino (e.g., methylamino, ethylamino etc.), (14) mono-C₆₋₁₄arylamino (e.g., phenylamino, 1-naphthylamino, 2-naphthylamino etc.),(15) mono-C₇₋₁₆ aralkylamino (e.g., benzylamino etc.), (16) di-C₁₋₆alkylamino (e.g., dimethylamino, diethylamino etc.), (17) di-C₆₋₁₄arylamino (e.g., diphenylamino etc.), (18) di-C₇₋₁₆ aralkylamino (e.g.,dibenzylamino etc.), (19) formyl, (20) C₁₋₆ alkyl-carbonyl (e.g.,acetyl, propionyl etc.), (21) C₆₋₁₄ aryl-carbonyl (e.g., benzoyl,1-naphthoyl, 2-naphthoyl etc.), (22) carboxyl, (23) C₁₋₆ alkoxy-carbonyl(e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,tert-butoxycarbonyl etc.), (24) C₆₋₁₄ aryloxy-carbonyl (e.g.,phenoxycarbonyl etc.), (25) carbamoyl, (26) thiocarbamoyl, (27)mono-C₁₋₆ alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl etc.),(28) di-C₁₋₆ alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl,ethylmethylcarbamoyl etc.), (29) C₆₋₁₄ aryl-carbamoyl (e.g.,phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl etc.), (30)C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.), (31)C₆₋₁₄ arylsulfonyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl,2-naphthylsulfonyl etc.), (32) C₁₋₆ alkylsulfinyl (e.g., methylsulfinyl,ethylsulfinyl etc.), (33) C₆₋₁₄ arylsulfinyl (e.g., phenylsulfinyl,1-naphthylsulfinyl, 2-naphthylsulfinyl etc.), (34) formylamino, (35)C₁₋₆ alkyl-carbonylamino (e.g., acetylamino etc.), (36) C₆₋₁₄aryl-carbonylamino (e.g., benzoylamino, naphthoylamino etc.), (37) C₁₋₆alkoxy-carbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino,propoxycarbonylamino, butoxycarbonylamino etc.), (38) C₁₋₆alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino etc.),(39) C₆₋₁₄ arylsulfonylamino (e.g., phenylsulfonylamino,2-naphthylsulfonylamino, 1-naphthylsulfonylamino etc.), (40) C₁₋₆alkyl-carbonyloxy (e.g., acetoxy, propionyloxy etc.), (41) C₆₋₁₄aryl-carbonyloxy (e.g., benzoyloxy, naphthylcarbonyloxy etc.), (42) C₁₋₆alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy,propoxycarbonyloxy, butoxycarbonyloxy etc.), (43) mono-C₁₋₆alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy etc.),(44) di-C₁₋₆ alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy,diethylcarbamoyloxy etc.), (45) C₆₋₁₄ aryl-carbamoyloxy (e.g.,phenylcarbamoyloxy; naphthylcarbamoyloxy etc.), (46) a 5- to 7-memberedsaturated cyclic amino (e.g., pyrrolidin-1-yl, piperidino,piperazin-1-yl, morpholino, thiomorpholino, hexahydroazepin-1-yl etc.)optionally containing, besides one nitrogen atom and carbon atom, 1 or 2kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom, (47) a 5- to 10-membered aromatic heterocyclicgroup (e.g., 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl,1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl,2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl,3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl etc.)containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom, (48)C₁₋₃ alkylenedioxy (e.g., methylenedioxy, ethylenedioxy etc.), and (49)C₃₋₇ cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl etc.) and the like.

When the above-mentioned hydrocarbon group is a cycloalkyl, an aryl oran aralkyl, the hydrocarbon group is optionally substituted by 1 to 5(preferably 1 to 3) substituents selected from (1) a halogen atom (e.g.,a fluorine atom, a chlorine atom, a bromine atom, an iodine atom etc.),(2) nitro, (3) cyano, (4) hydroxy, (5) C₁₋₆ alkoxy (e.g., methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy,hexyloxy, fluoromethoxy etc.) optionally having 1 to 3 halogen atoms(e.g., a fluorine atom, a chlorine atom, a bromine atom, an iodineatom), (6) C₆₋₁₄ aryloxy (e.g., phenyloxy, naphthyloxy etc.), (7) C₇₋₁₆aralkyloxy (e.g., benzyloxy, phenethyloxy, diphenylmethyloxy,1-naphthylmethyloxy, 2-naphthylmethyloxy, 2,2-diphenylethyloxy,3-phenylpropyloxy, 4-phenylbutyloxy, 5-phenylpentyloxy etc.), (8)mercapto, (9) C₁₋₆ alkylthio (e.g., methylthio, difluoromethylthio,trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio,4,4,4-trifluorobutylthio, pentylthio, hexylthio etc.) optionally having1 to 3 halogen atoms (e.g., a fluorine atom, a chlorine atom, a bromineatom, an iodine atom), (10) C₆₋₁₄ arylthio (e.g., phenylthio,naphthylthio etc.), (11) C₇₋₁₆ aralkylthio (e.g., benzylthio,phenethylthio, diphenylmethylthio, 1-naphthylmethylthio,2-naphthylmethylthio, 2,2-diphenylethylthio, 3-phenylpropylthio,4-phenylbutylthio, 5-phenylpentylthio etc.), (12) amino, (13) mono-C₁₋₆alkylamino (e.g., methylamino, ethylamino etc.), (14) mono-C₆₋₁₄arylamino (e.g., phenylamino, 1-naphthylamino, 2-naphthylamino etc.),(15) mono-C₇₋₁₆ aralkylamino (e.g., benzylamino etc.), (16) di-C₁₋₆alkylamino (e.g., dimethylamino, diethylamino etc.), (17) di-C₆₋₁₄arylamino (e.g., diphenylamino etc.), (18) di-C₇₋₁₆ aralkylamino (e.g.,dibenzylamino etc.), (19) formyl, (20) C₁₋₆ alkyl-carbonyl (e.g.,acetyl, propionyl etc.), (21) C₆₋₁₄ aryl-carbonyl (e.g., benzoyl,1-naphthoyl, 2-naphthoyl etc.), (22) carboxyl, (23) C₁₋₆ alkoxy-carbonyl(e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,tert-butoxycarbonyl etc.), (24) C₆₋₁₄ aryloxy-carbonyl (e.g.,phenoxycarbonyl etc.), (25) carbamoyl, (26) thiocarbamoyl, (27)mono-C₁₋₆ alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl etc.),(28) di-C₁₋₆ alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl,ethylmethylcarbamoyl etc.), (29) C₆₋₁₄ aryl-carbamoyl (e.g.,phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl etc.), (30)C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl,trifluoromethylsulfonyl etc.) optionally having 1 to 3 halogen atoms(e.g., a fluorine atom, a chlorine atom, a bromine atom, an iodineatom), (31) C₆₋₁₄ arylsulfonyl (e.g., phenylsulfonyl,1-naphthylsulfonyl, 2-naphthylsulfonyl etc.), (32) C₁₋₆ alkylsulfinyl(e.g., methylsulfinyl, ethylsulfinyl etc.), (33) C₆₋₁₄ arylsulfinyl(e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl etc.),(34) formylamino, (35) C₁₋₆ alkyl-carbonylamino (e.g., acetylaminoetc.), (36) C₆₋₁₄ aryl-carbonylamino (e.g., benzoylamino, naphthoylaminoetc.), (37) C₁₋₆ alkoxy-carbonylamino (e.g., methoxycarbonylamino,ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino etc.),(38) C₁₋₆ alkylsulfonylamino (e.g., methylsulfonylamino,ethylsulfonylamino etc.), (39) C₆₋₁₄ arylsulfonylamino (e.g.,phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylaminoetc.), (40) C₁₋₆ alkyl-carbonyloxy (e.g., acetoxy, propionyloxy etc.),(41) C₆₋₁₄ aryl-carbonyloxy (e.g., benzoyloxy, naphthylcarbonyloxyetc.), (42) C₁₋₆ alkoxy-carbonyloxy (e.g., methoxycarbonyloxy,ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy etc.), (43)mono-C₁₋₆ alkyl-carbamoyloxy (e.g., methylcarbamoyloxy,ethylcarbamoyloxy etc.), (44) di-C₁₋₆ alkyl-carbamoyloxy (e.g.,dimethylcarbamoyloxy, diethylcarbamoyloxy etc.), (45) C₆₋₁₄aryl-carbamoyloxy (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy etc.),(46) a 5- to 7-membered saturated cyclic amino (e.g., pyrrolidin-1-yl,piperidino, piperazin-1-yl, morpholino, thiomorpholino,hexahydroazepin-1-yl etc.) optionally containing, besides one nitrogenatom and carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected froma nitrogen atom, a sulfur atom and an oxygen atom, (47) a 5- to10-membered aromatic heterocyclic group (e.g., 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl,5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl,5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl,2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl,3-benzo[b]furanyl etc.) containing, besides carbon atom, 1 or 2 kinds of1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom, (48) C₁₋₃ alkylenedioxy (e.g., methylenedioxy,ethylenedioxy etc.), (49) C₃₋₇ cycloalkyl (e.g., cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.), (50) C₁₋₆ alkylgroup (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl,n-hexyl, isohexyl etc.) optionally having 1 to 3 halogen atoms (e.g., afluorine atom, a chlorine atom, a bromine atom, an iodine atom) orhydroxy groups, (51) a C₂₋₆ alkenyl group (e.g., allyl, isopropenyl,isobutenyl, 1-methylallyl, 2-pentenyl, 2-hexenyl etc.) optionally having1 to 3 halogen atoms (e.g., a fluorine atom, a chlorine atom, a bromineatom, an iodine atom), (52) a C₂₋₆ alkynyl group (e.g., propargyl,2-butynyl, 3-butynyl, 3-pentynyl, 3-hexynyl etc.), (53) mono-C₃₋₇cycloalkyl-carbamoyl (e.g., cyclopropylcarbamoyl, cyclobutylcarbamoyletc.), and (54) a 5 to 10-membered heterocyclyl-carbonyl (e.g.,4-morpholinocarbonyl etc.) containing, besides carbon atom, one or twokinds of 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atomand an oxygen atom and the like.

In the present specification, the substituent of the “optionallysubstituted hydrocarbon group” does not include an oxo group.

As the “optionally halogenated C₁₋₆ alkyl-carbonyl” for R⁴⁰, forexample, C₁₋₆ alkyl-carbonyl optionally having 1 to 5, preferably 1 to 3halogen atoms (e.g., a fluorine atom, a chlorine atom, a bromine atom,an iodine atom and the like) at substitutable positions and the like canbe mentioned. Specific examples include, for example, acetyl,monochloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl,pentanoyl, hexanoyl and the like can be mentioned.

As the “optionally halogenated C₁₋₆ alkylsulfonyl” for R⁴⁰, for example,C₁₋₆ alkylsulfonyl optionally having 1 to 5, preferably 1 to 3 halogenatoms (e.g., a fluorine atom, a chlorine atom, a bromine atom, an iodineatom and the like) at substitutable positions and the like can bementioned. Specific examples include, for example, methylsulfonyl,difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl,propylsulfonyl, isopropylsulfonyl, butylsulfonyl,4,4,4-trifluorobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl,pentylsulfonyl, hexylsulfonyl and the like can be mentioned.

As the “divalent C₁₋₆ aliphatic hydrocarbon group” of the aforementioned“divalent C₁₋₆ aliphatic hydrocarbon group optionally havingsubstituent(s)”, an alkylene group, an alkenylene group, an alkynylenegroup can be mentioned, for example,

(1) a C₁₋₆ alkylene (e.g., —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—,—(CH₂)₅—, —(CH₂)₆—, —CH(CH₃)—, —C(CH₃)₂—, —(CH(CH₃))₂—, —(CH₂)₂C(CH₃)₂—,—(CH₂)₃C(CH₃)₂— and the like);(2) a C₂₋₆ alkenylene (e.g., —CH═CH—, —CH₂—CH═CH—, —CH═CH—CH₂—,—CH═CH—CH₂—CH₂—, —C(CH₃)₂—CH═CH—, —CH₂—CH═CH—CH₂—, —CH₂—CH₂—CH═CH—,—CH═CH—CH═CH—, —CH═CH—CH₂—CH₂—CH₂— and the like);(3) a C₂₋₆ alkynylene (e.g., —C≡C—, —CH₂—C≡C—, —CH₂—C≡C—CH₂—CH₂— and thelike) and the like can be mentioned.

As the “substituent” of the “divalent C₁₋₆ aliphatic hydrocarbon groupoptionally having substituent(s)”, for example, those similar to thesubstituents of the alkyl, alkenyl or alkynyl exemplified as theaforementioned “optionally substituted hydrocarbon group” for R⁴⁰, canbe mentioned, particularly, halogen atom (e.g., a fluorine atom, achlorine atom, a bromine atom, an iodine atom), hydroxy and the like arepreferable. The number of the substituents is, for example, 1 to 5,preferably 1 to 3.

As preferable examples of the “spacer having 1 to 20 atoms in the mainchain”

(1) an optionally substituted alkylene group:specifically, a C₁₋₂₀ alkylene (e.g., —CH₂—, —(CH₂)₂—, —(CH₂)₃—,—CH(OH)— (CH₂)₂—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —CHCH₃—, —C(CH₃)₂—,—CH(CF₃)—, —(CH(CH₃))₂—, —(CF₂)₂—, —(CH₂)₂C(CH₃)₂—, —(CH₂)₃C(CH₃)₂—,—(CH₂)₇—, —(CH₂)₈—, —(CH₂)₉—, —(CH₂)₁₀—, —(CH₂)₁₁—, —(CH₂)₁₂—,—(CH₂)₁₃—, —(CH₂)₁₄—, —(CH₂)₁₅—, —(CH₂)₁₆—, —(CH₂)₁₇—, —(CH₂)₁₈—,—(CH₂)₁₉—, —(CH₂)₂₀— and the like) optionally having 1 to 3 substituents(preferably, halogen atom, hydroxy and the like); (2) an optionallysubstituted alkenylene group:specifically, a C₂₋₂₀ alkenylene (e.g., —CH═CH—, —CH₂—CH═CH—,—CH═CH—CH₂—, —CH═CH—CH₂—CH₂—, —CH₂—CF═CH—, —C(CH₃)₂—CH═CH—,—CH₂—CH═CH—CH₂—, —CH₂—CH₂—CH═CH—, —CH═CH—CH═CH—, —CH═CH—CH₂—CH₂—CH₂— andthe like) optionally having 1 to 3 substituents (preferably, halogenatom, hydroxy and the like); (3) an optionally substituted alkynylenegroup:specifically, a C₂₋₂₀ alkynylene (e.g., —C≡C—, —CH₂—C≡C—,—CH₂—C≡C—CH₂—CH₂— and the like) optionally having 1 to 3 substituents(preferably, halogen atom, hydroxy and the like); (4)-(CH₂)_(w1a)O(CH₂)_(w2a)—, —(CH₂)_(w1a)S(CH₂)_(w2a)—,—(CH₂)_(w1a)CO(CH₂)_(w2a)—, —(CH₂)_(w1a)SO(CH₂)_(w2a)—,—(CH₂)_(w1a)SO₂(CH₂)_(w2a)—, —(CH₂)_(w1a)NR⁴⁰(CH₂)_(w2a)—; (5)—(CH₂)_(w3a)CO—, —(CH₂)_(w3a)CONR⁴⁰(CH₂)_(w4a)—,—(CH₂)_(w3a)NR⁴⁰CO(CH₂)_(w4a)—, —(CH₂)_(w3a)SO₂NR⁴⁰(CH₂)_(w4a)—,—(CH₂)_(w3a)NR⁴⁰SO₂(CH₂)_(w4a)—, —(CH₂)_(w3a)COO(CH₂)_(w4a)—; (6)—(CH₂)_(w5a)NR⁴⁰CONR^(40b)(CH₂)_(w6a)—;wherein R⁴⁰ is as defined above; R^(40b) is as defined as R⁴⁰; w1a andw2a are each an integer of 0 to 19, and w1a+w2a is 0 to 19; w3a and w4aare each an integer of 0 to 18, and w3a+w4a is 0 to 18; w5a and w6a areeach an integer of 0 to 17, and w5a+w6a is 0 to 17,and the like can be mentioned.

As the aforementioned “spacer having 1 to 20 atoms in the main chain”,the following “spacer having 1 to 8 atoms in the main chain” ispreferable.

(1) a C₁₋₈ alkylene (e.g., —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —CH(OH)—(CH₂)₂—,—(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —CHCH₃—, —C(CH₃)₂—, —CH(CF₃)—,—(CH(CH₃))₂—, —(CF₂)₂—, —(CH₂)₂C(CH₃)₂—, —(CH₂)₃C(CH₃)₂— and the like)optionally having 1 to 3 substituents (preferably, halogen atom, hydroxyand the like); (2) a C₂₋₈ alkenylene (e.g., —CH═CH—, —CH₂—CH═CH—,—CH═CH—CH₂—, —CH═CH—CH₂—CH₂—, —CH₂—CF═CH—, —C(CH₃)₂—CH═CH—,—CH₂—CH═CH—CH₂—, —CH₂—CH₂—CH═CH—, —CH═CH—CH═CH—, —CH═CH—CH₂—CH₂—CH₂— andthe like) optionally having 1 to 3 substituents (preferably, halogenatom, hydroxy and the like); (3) a C₂₋₈ alkynylene (e.g., —C≡C—,—CH₂—C≡C—, —CH₂—C≡C—CH₂—CH₂— and the like) optionally having 1 to 3substituents (preferably, halogen atom, hydroxy and the like); (4)—(CH₂)_(w1)O(CH₂)_(w2)—, —(CH₂)_(w1)S(CH₂)_(w2)—,—(CH₂)_(w1)CO(CH₂)_(w2)—, —(CH₂)_(w1)SO(CH₂)_(w2)—, —(CH₂)_(w1)SO₂(CH₂)_(w2)—, —(CH₂)_(w1)NR⁴⁰(CH₂)_(w2)—; (5) —(CH₂)_(w3)CO—,—(CH₂)_(w3)CONR⁴⁰(CH₂)_(w4)—, —(CH₂)_(w3)NR⁴⁰CO(CH₂)_(w4)—,—(CH₂)_(w3)SO₂NR⁴⁰(CH₂)_(w4)—, —(CH₂)_(w3)NR⁴⁰SO₂CH₂)_(w4)—,—(CH₂)_(w3)COO(CH₂)_(w4)—; (6) —(CH₂)_(w5)NR⁴⁰CONR^(40b)(CH₂)_(w6)—;wherein R⁴⁰ is as defined above; R^(40b) is as defined as R⁴⁰; w1 and w2are each an integer of 0 to 5, and w1+w2 is 0 to 7; w3 and w4 are eachan integer of 0 to 4, and w3+w4 is 0 to 6; w5 and w6 are each an integerof 0 to 3, and w5+w6 is 0 to 5, and the like can be mentioned.

The “spacer having 1 to 20 atoms in the main chain” is preferably thefollowing (1) to (6).

(1) —SO₂—; (2) —SO₂—N(R⁷)— wherein R⁷ is a hydrogen atom or anoptionally substituted hydrocarbon group, and as the “optionallysubstituted hydrocarbon group” for R⁷, those similar to theaforementioned “optionally substituted hydrocarbon group” for R⁴⁰ can bementioned; (3) —N(R⁸)—SO₂— wherein R⁸ is a hydrogen atom or anoptionally substituted hydrocarbon group, and as the “optionallysubstituted hydrocarbon group” for R⁸, those similar to theaforementioned “optionally substituted hydrocarbon group” for R⁴⁰ can bementioned; (4) —N(R⁹)— wherein R⁹ is a hydrogen atom or an optionallysubstituted hydrocarbon group, and as the “optionally substitutedhydrocarbon group” for R⁹, those similar to the aforementioned“optionally substituted hydrocarbon group” for R⁴⁰ can be mentioned; (5)—O—; (6) an optionally substituted alkylene group, preferably a C₁₋₈alkylene (e.g., —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —CH(OH)—(CH₂)₂—, —(CH₂)₄—,—(CH₂)₅—, —(CH₂)₆—, —CHCH₃—, —C(CH₃)₂—, —CH(CF₃)—, —(CH(CH₃))₂—,—(CF₂)₂—, —(CH₂)₂C(CH₃)₂—, —(CH₂)₃C(CH₃)₂— and the like) optionallyhaving 1 to 3 substituents (preferably, halogen atom, hydroxy and thelike).

In the formula (I), X is preferably —SO₂—, —SO₂—N(R⁷)— (wherein R⁷ is asdefined above), —N(R⁸)—SO₂— (wherein R⁸ is as defined above), —N(R⁹)—(wherein R⁹ is as defined above) or —O—, particularly preferably —SO₂—.

Y is preferably a bond or a C₁₋₈ alkylene (e.g., —CH₂—, —(CH₂)₂,—(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —CHCH₃—, —C(CH₃)₂—,—(CH(CH₃))₂—, —(CH₂)₂C(CH₃)₂—, —(CH₂)₃C(CH₃)₂— and the like).

In the aforementioned formula (I), R¹ is an optionally substitutedhydrocarbon group or an optionally substituted heterocyclic group.

As the “optionally substituted hydrocarbon group”, those similar to theaforementioned “optionally substituted hydrocarbon group” for R⁴⁰ can bementioned.

As the “heterocyclic group” of the “optionally substituted heterocyclicgroup”, for example, a 3 to 8-membered heterocyclic group (preferably 5or 6-membered heterocyclic group) containing 1 to 4 heteroatoms selectedfrom a nitrogen atom (optionally oxidized), an oxygen atom, a sulfuratom (optionally mono- or di-oxidized) and the like; or a group formedby condensing a 3 to 8-membered heterocyclic group (preferably 5 or6-membered heterocyclic group) containing 1 to 4 heteroatoms selectedfrom a nitrogen atom (optionally oxidized), an oxygen atom, a sulfuratom (optionally mono- or di-oxidized) and the like, and a benzene ringor a 3 to 8-membered heterocyclic group (preferably 5 or 6-memberedheterocyclic group) containing 1 to 4 heteroatoms selected from anitrogen atom (optionally oxidized), an oxygen atom, a sulfur atom(optionally mono- or di-oxidized) and the like, preferably a groupformed by condensing the 5 or 6-membered heterocyclic group and a 5 or6-membered ring containing 1 to 4 heteroatoms selected from a nitrogenatom (optionally oxidized), an oxygen atom, a sulfur atom (optionallymono- or di-oxidized) and the like, can be mentioned.

To be specific, aziridinyl (e.g., 1- or 2-aziridinyl), azirinyl (e.g.,1- or 2-azirinyl), azetyl (e.g., 2-, 3- or 4-azetyl), azetidinyl (e.g.,1-, 2- or 3-azetidinyl), perhydroazepinyl (e.g., 1-, 2-, 3- or4-perhydroazepinyl), perhydroazocinyl (e.g., 1-, 2-, 3-, 4- or5-perhydroazocinyl), pyrrolyl (e.g., 1-, 2- or 3-pyrrolyl), pyrazolyl(e.g., 1-, 3-, 4- or 5-pyrazolyl), imidazolyl (e.g., 1-, 2-, 4- or5-imidazolyl), triazolyl (e.g., 1,2,3-triazol-1-, 4- or -5-yl,1,2,4-triazol-1-, 3-, 4- or 5-yl), tetrazolyl (e.g., tetrazol-1-, 2- or5-yl), furyl (e.g., 2- or 3-furyl), thienyl (e.g., 2- or 3-thienyl),thienyl wherein the sulfur atom is oxidized (e.g., 2- or3-thienyl-1,1-dioxide), oxazolyl (e.g., 2-, 4- or 5-oxazolyl),isoxazolyl (e.g., 3-, 4- or 5-isoxazolyl), oxadiazolyl (e.g.,1,2,3-oxadiazol-4- or 5-yl, 1,2,4-oxadiazol-3- or 5-yl,1,2,5-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl), thiazolyl (e.g., 2-, 4- or5-thiazolyl), isothiazolyl (e.g., 3-, 4- or 5-isothiazolyl),thiadiazolyl (e.g., 1,2,3-thiadiazol-4- or 5-yl, 1,2,4-thiadiazol-3- or5-yl, 1,2,5-thiadiazol-3-yl, 1,3,4-thiadiazol-2-yl), pyrrolidinyl (e.g.,1-, 2- or 3-pyrrolidinyl), pyridyl (e.g., 2-, 3- or 4-pyridyl), pyridylwherein the nitrogen atom is oxidized (e.g., 2-, 3- or4-pyridyl-N-oxide), pyridazinyl (e.g., 3- or 4-pyridazinyl), pyridazinylwherein one or both of the nitrogen atom is oxidized (e.g., 3-, 4-, 5-or 6-pyridazinyl-N-oxide), pyrimidinyl (e.g., 2-, 4- or 5-pyrimidinyl),pyrimidinyl wherein one or both of the nitrogen atoms is(are) oxidized(e.g., 2-, 4-, 5- or 6-pyrimidinyl-N-oxide), pyrazinyl, piperidinyl(e.g., 1-, 2-, 3- or 4-piperidinyl), piperazinyl (e.g., 1- or2-piperazinyl), indolyl (e.g., 3H-indol-2-, 3-, 4-, 5-, 6- or 7-yl),pyranyl (e.g., 2-, 3- or 4-pyranyl), thiopyranyl (e.g., 2-, 3- or4-thiopyranyl), thiopyranyl wherein the sulfur atom is oxidized (e.g.,2-, 3- or 4-thiopyranyl-1,1-dioxide), morpholinyl (e.g., 2-, 3- or4-morpholinyl), thiomorpholinyl, quinolyl (e.g., 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolyl), isoquinolyl, pyrido[2,3-d]pyrimidinyl (e.g.,pyrido[2,3-d]pyrimidin-2-yl), naphthyridinyl such as 1,5-, 1,6-, 1,7-,1,8-, 2,6- or 2,7-naphthyridinyl and the like (e.g., 1,5-naphthyridin-2-or 3-yl), thieno[2,3-d]pyridyl (e.g., thieno[2,3-d]pyridin-3-yl),pyrazinoquinolyl (e.g., pyrazino[2,3-d]quinolin-2-yl), chromenyl (e.g.,2H-chromen-2- or 3-yl), 2-benzo[b]thienyl, 3-benzo[b]thienyl,2-benzo[b]furanyl, 3-benzo[b]furanyl, 2,3-dihydro-1-benzofuranyl,2,1,3-benzothiadiazolyl, 2,3-dihydro-1,4-benzodioxin-5- or -6-yl,1,3-benzothiazol-6-yl, 1,1-dioxido-2,3-dihydro-1-benzothien-6-yl,1-benzothienyl and the like can be used.

As the “substituent” of the heterocyclic group, those similar to thesubstituents of the cycloalkyl, aryl or aralkyl exemplified as theabove-mentioned “hydrocarbon group” for R⁴⁰, can be mentioned. Thenumber of the substituents is, for example, 1 to 5, preferably 1 to 3.

R¹ is preferably an optionally substituted alkyl group, an optionallysubstituted aryl group, an optionally substituted aralkyl group or anoptionally substituted thienyl group, more preferably an optionallysubstituted alkyl group, an optionally substituted aryl group or anoptionally substituted aralkyl group, particularly preferably anoptionally substituted aryl group. To be specific, R¹ is preferably [1]C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl etc.), [2] a C₆₋₁₄ aryl group(e.g., phenyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3)substituents selected from (i) halogen (e.g., fluorine, chlorine,bromine, iodine), (ii) hydroxy, (iii) cyano, (iv) C₁₋₆ alkyl (e.g.,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5(preferably 1 to 3) halogens (e.g., fluorine, chlorine, bromine,iodine), (v) C₁₋₆alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine) and (vi) phenyl, or [3] an (unsubstituted)thienyl group,

particularly preferably a C₆₋₁₄ aryl group (e.g., phenyl etc.)optionally substituted by 1 to 5 (preferably 1 to 3) substituentsselected from halogen, hydroxy and C₁₋₆ alkyl.

In the aforementioned formula (I), R², R³ and R⁴ are the same ordifferent and each is a hydrogen atom or an optionally substitutedhydrocarbon group, an optionally substituted thienyl group, anoptionally substituted benzo[b]thienyl group, an optionally substitutedfuryl group, an optionally substituted pyridyl group, an optionallysubstituted pyrazolyl group, an optionally substituted pyrimidinylgroup, an acyl group, a halogen atom, a cyano group or a nitro group,preferably, a hydrogen atom or an optionally substituted hydrocarbongroup, an optionally substituted thienyl group, an optionallysubstituted benzo[b]thienyl group, an optionally substituted furylgroup, an optionally substituted pyridyl group, an acyl group, a halogenatom, a cyano group or a nitro group.

As the “optionally substituted hydrocarbon group” for R², R³ or R⁴,those similar to the aforementioned “optionally substituted hydrocarbongroup” for R⁴⁰ can be mentioned.

As the “thienyl group” of the “optionally substituted thienyl group” forR², R³ or R⁴, 2- or 3-thienyl can be mentioned.

As the “substituent” of the thienyl group, those similar to thesubstituents of the cycloalkyl, aryl or aralkyl exemplified as theabove-mentioned “hydrocarbon group” for R⁴⁰ can be mentioned. The numberof the substituents is 1 to 3.

As the “benzo[b]thienyl group” of the “optionally substitutedbenzo[b]thienyl group” for R², R³ or R⁴, 2- or 3-benzo[b]thienyl can bementioned.

As the “substituent” of the benzo[b]thienyl group, those similar to thesubstituents of the cycloalkyl, aryl or aralkyl exemplified as theabove-mentioned “hydrocarbon group” for R⁴⁰ can be mentioned. The numberof the substituents is, for example, 1 to 5, preferably 1 to 3.

As the “furyl group” of the “optionally substituted furyl group” for R²,R³ or R⁴, 2- or 3-furyl can be mentioned.

As the “substituent” of the furyl group, those similar to thesubstituents of the cycloalkyl, aryl or aralkyl exemplified as theabove-mentioned “hydrocarbon group” for R⁴⁰ can be mentioned. The numberof the substituents is 1 to 3.

As the “pyridyl group” of the “optionally substituted pyridyl group” forR², R³ or R⁴, 2-, 3- or 4-pyridyl can be mentioned.

As the “substituent” of the pyridyl group, those similar to thesubstituents of the cycloalkyl, aryl or aralkyl exemplified as theabove-mentioned “hydrocarbon group” for R⁴⁰ can be mentioned. The numberof the substituents is 1 to 3.

As the “pyrazolyl group” of the “optionally substituted pyrazolyl group”for R², R³ or R⁴, 3- or 4-pyrazolyl can be mentioned.

As the “substituent” of the pyrazolyl group, those similar to thesubstituents of the cycloalkyl, aryl or aralkyl exemplified as theabove-mentioned “hydrocarbon group” for R⁴⁰ can be mentioned. The numberof the substituents is 1 to 3.

As the “pyrimidinyl group” of the “optionally substituted pyrimidinylgroup” for R², R³ or R⁴, 2-, 4- or 5-pyrimidinyl can be mentioned.

As the “substituent” of the pyrimidinyl group, those similar to thesubstituents of the cycloalkyl, aryl or aralkyl exemplified as theabove-mentioned “hydrocarbon group” for R⁴⁰ can be mentioned. The numberof the substituents is 1 to 3.

As the “acyl group” for R², R³ or R⁴, an acyl group having 1 to 20carbon atoms, which is derived from an organic carboxylic acid can bementioned. For example, C₁₋₇ alkanoyl groups (e.g., formyl; C₁₋₆alkyl-carbonyl such as acetyl, propionyl, butyryl, isobutyryl,pentanoyl, hexanoyl, heptanoyl and the like; etc.), C₆₋₁₄ aryl-carbonylgroups (e.g., benzoyl, naphthalenecarbonyl etc.), C₁₋₆ alkoxy-carbonylgroups (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl etc.), C₆₋₁₄ aryloxy-carbonylgroups (e.g., phenoxycarbonyl group), C₇₋₁₉ aralkyl-carbonyl groups(e.g., phenyl-C₁₋₄ alkylcarbonyl such as benzylcarbonyl,phenethylcarbonyl, phenylpropylcarbonyl and the like, naphthyl-C₁₋₄alkylcarbonyl such as benzhydrylcarbonyl, naphthylethylcarbonyl and thelike, etc.), C₇₋₁₉ aralkyloxy-carbonyl groups (e.g., phenyl-C₁₋₄alkyloxycarbonyl such as benzyloxycarbonyl and the like, etc.), 5- or6-membered heterocyclyl-carbonyl group or condensedheterocyclyl-carbonyl groups thereof (e.g., pyrrolylcarbonyl such as 2-or 3-pyrrolylcarbonyl and the like; pyrazolylcarbonyl such as 3-, 4- or5-pyrazolylcarbonyl and the like; imidazolylcarbonyl such as 2-, 4- or5-imidazolylcarbonyl and the like; triazolylcarbonyl such as1,2,3-triazol-4-ylcarbonyl, 1,2,4-triazol-3-ylcarbonyl and the like;tetrazolylcarbonyl such as 1H- or 2H-tetrazol-5-ylcarbonyl and the like;furylcarbonyl such as 2- or 3-furylcarbonyl and the like;thienylcarbonyl such as 2- or 3-thienylcarbonyl and the like;oxazolylcarbonyl such as 2-, 4- or 5-oxazolylcarbonyl and the like;isoxazolylcarbonyl such as 3-, 4- or 5-isoxazolylcarbonyl and the like;oxadiazolylcarbonyl such as 1,2,3-oxadiazol-4- or 5-ylcarbonyl,1,2,4-oxadiazol-3- or 5-ylcarbonyl, 1,2,5-oxadiazol-3- or 4-ylcarbonyl,1,3,4-oxadiazol-2-ylcarbonyl and the like; thiazolylcarbonyl such as 2-,4- or 5-thiazolylcarbonyl and the like; isothiazolylcarbonyl such as 3-,4- or 5-isothiazolylcarbonyl and the like; thiadiazolylcarbonyl such as1,2,3-thiadiazol-4- or 5-ylcarbonyl, 1,2,4-thiadiazol-3- or5-ylcarbonyl, 1,2,5-thiadiazol-3- or 4-ylcarbonyl,1,3,4-thiadiazol-2-ylcarbonyl and the like; pyrrolidinylcarbonyl such as2- or 3-pyrrolidinylcarbonyl and the like; pyridylcarbonyl such as 2-,3- or 4-pyridylcarbonyl and the like; pyridylcarbonyl wherein nitrogenatom is oxidized such as 2-, 3- or 4-pyridyl-N-oxidocarbonyl and thelike; pyridazinylcarbonyl such as 3- or 4-pyridazinylcarbonyl and thelike; pyridazinyl wherein one or both nitrogen atoms are oxidized, suchas 3-, 4-, 5- or 6-pyridazinyl-N-oxidocarbonyl and the like;pyrimidinylcarbonyl such as 2-, 4- or 5-pyrimidinylcarbonyl and thelike; pyrimidinylcarbonyl wherein one or both nitrogen atoms areoxidized, such as 2-, 4-, 5- or 6-pyrimidinyl-N-oxidocarbonyl and thelike; pyrazinylcarbonyl; piperidinylcarbonyl such as 2-, 3- or4-piperidinylcarbonyl and the like; piperazinylcarbonyl; indolylcarbonylsuch as 3H-indol-2- or 3-ylcarbonyl and the like; pyranylcarbonyl suchas 2-, 3- or 4-pyranylcarbonyl and the like; thiopyranylcarbonyl such as2-, 3- or 4-thiopyranylcarbonyl and the like; quinolylcarbonyl such as3-, 4-, 5-, 6-, 7- or 8-quinolylcarbonyl and the like;isoquinolylcarbonyl; pyrido[2,3-d]pyrimidinylcarbonyl (e.g.,pyrido[2,3-d]pyrimidin-2-ylcarbonyl); naphthyridinylcarbonyl (e.g.,1,5-naphthyridin-2- or 3-ylcarbonyl) such as 1,5-, 1,6-, 1,7-, 1,8-,2,6- or 2,7-naphthyridinylcarbonyl and the like;thieno[2,3-d]pyridylcarbonyl (e.g., thieno[2,3-d]pyridin-3-ylcarbonyl);pyrazinoquinolylcarbonyl (e.g., pyrazino[2,3-b]quinolin-2-ylcarbonyl); a5- or 6-membered heterocyclyl-carbonyl group (e.g., chromenylcarbonyl(e.g., 2H-chromen-2- or 3-ylcarbonyl etc.) and the like) containing 1 to4 hetero atoms such as nitrogen atom (optionally oxidized), oxygen atom,sulfur atom (optionally mono or dioxidized) and the like), a 5- or6-membered heterocyclyl-acetyl group (e.g., 5- or 6-memberedheterocyclyl-acetyl group containing 1 to 4 hetero atoms such asnitrogen atom (optionally oxidized), oxygen atom, sulfur atom(optionally mono or dioxidized) and the like), such as 2-pyrrolylacetyl,3-imidazolylacetyl, 5-isoxazolylacetyl and the like, and the like can beused.

As regards the substituent of acyl group, for example, when theabove-mentioned acyl group is an alkanoyl group or alkoxy-carbonylgroup, the acyl group is optionally substituted by 1 to 3 selected fromalkylthio groups (e.g., C₁₋₄ alkylthio such as methylthio, ethylthio,n-propylthio, isopropylthio and the like, and the like), halogen (e.g.,fluorine, chlorine, bromine, iodine), alkoxy groups (e.g., C₁₋₆ alkoxysuch as methoxy, ethoxy, n-propoxy, tert-butoxy, n-hexyloxy and thelike, and the like), a nitro group, alkoxy-carbonyl groups (e.g., C₁₋₆alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl and the like,and the like), alkylamino group (e.g., mono- or di-C₁₋₆ alkylamino suchas methylamino, ethylamino, n-propylamino, n-butylamino,tert-butylamino, n-pentylamino, n-hexylamino, dimethylamino,diethylamino, methylethylamino, di-(n-propyl)amino, di-(n-butyl)aminoand the like, and the like), alkoxyimino groups (e.g., C₁₋₆ alkoxyiminosuch as methoxyimino, ethoxyimino, n-propoxyimino, tert-butoxyimino,n-hexyloxy-imino and the like, and the like) and hydroxyimino.

When the above-mentioned acyl group is an aryl-carbonyl group, anaryloxy-carbonyl group, an aralkyl-carbonyl group, an aralkyloxycarbonylgroup, a 5- or 6-membered heterocyclyl-carbonyl group or a 5- or6-membered heterocyclyl-acetyl group, the acyl group is optionallysubstituted by 1 to 5 (preferably 1 to 3) selected from alkyl groups(e.g., C₁₋₆ alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl,neopentyl, n-hexyl, isohexyl and the like, C₃₋₆ cycloalkyl such ascyclohexyl and the like, and the like), alkenyl groups (e.g., C₂₋₆alkenyl such as allyl, isopropenyl, isobutenyl, 1-methylallyl,2-pentenyl, 2-hexenyl and the like, and the like), alkynyl groups (e.g.,C₂₋₆ alkynyl such as propargyl, 2-butynyl, 3-butynyl, 3-pentynyl,3-hexynyl and the like, and the like), alkoxy groups (e.g., C₁₋₆ alkoxysuch as methoxy, ethoxy, n-propoxy, tert-butoxy, n-hexyloxy and thelike, and the like), acyl groups [e.g., C₁₋₇ alkanoyl such as formyl,acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyland the like; C₆₋₁₄ aryl-carbonyl such as benzoyl, naphthalenecarbonyland the like; C₁₋₆ alkoxy-carbonyl such as methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl and the like;C₆₋₁₄ aryloxy-carbonyl such as phenoxycarbonyl and the like; C₇₋₁₉aralkyl-carbonyl such as phenyl-C₁₋₄ alkyl-carbonyl (e.g.,benzylcarbonyl, phenethylcarbonyl, phenylpropylcarbonyl and the like)and the like; C₇₋₁₉ aralkyloxy-carbonyl such as phenyl-C₁₋₄alkyloxy-carbonyl (e.g., benzyloxycarbonyl and the like) and the like,and the like], nitro, amino, hydroxy, cyano, sulfamoyl, mercapto,halogen (e.g., fluorine, chlorine, bromine, iodine), and alkylthiogroups (C₁₋₄ alkylthio such as methylthio, ethylthio, n-propylthio,isobutylthio and the like, and the like).

As the “halogen atom” for R², R³ or R⁴, fluorine atom, chlorine atom,bromine atom and iodine atom can be mentioned.

R² is preferably a hydrogen atom, an optionally substituted hydrocarbongroup, an optionally substituted thienyl group, an optionallysubstituted benzo[b]thienyl group, an optionally substituted furylgroup, an optionally substituted pyridyl group, an optionallysubstituted pyrazolyl group or an optionally substituted pyrimidinylgroup, more preferably a hydrogen atom, an optionally substitutedhydrocarbon group, an optionally substituted thienyl group, anoptionally substituted benzo[b]thienyl group, an optionally substitutedfuryl group or an optionally substituted pyridyl group, further morepreferably a hydrogen atom or an optionally substituted hydrocarbongroup, particularly preferably a hydrogen atom or an optionallysubstituted aryl group.

To be specific, R² is preferably

[1] a hydrogen atom, [2] C₆₋₁₄ aryl group (e.g., phenyl group)optionally substituted by 1 to 5 (preferably 1 to 3) substituentsselected from (i) a halogen atom (e.g., a fluorine atom, a chlorineatom, a bromine atom, an iodine atom), (ii) cyano, (iii) aminooptionally substituted by 1 or 2 selected from C₁₋₆ alkyl (e.g., methyl,ethyl etc.) and acetyl, (iv) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.)optionally substituted by 1 to 5 (preferably 1 to 3) halogens (e.g.,fluorine, chlorine, bromine, iodine), (V) C₁₋₆ alkoxy (e.g., methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy,hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3)halogens (e.g., fluorine, chlorine, bromine, iodine), (vi) phenoxy,(vii) C₁₋₆ alkylthio (e.g., methylthio, ethylthio etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine), (viii) acetyl and (ix) aminocarbonyl, or [3]thienyl group, benzo[b]thienyl group, furyl group, pyridyl group,pyrazolyl group or pyrimidinyl group, each of which is optionallysubstituted by 1 to 3 substituents selected from C₁₋₆ alkoxy (e.g.,methoxy, ethoxy etc.) and C₁₋₆ alkyl (e.g., methyl, ethyl, n-propyl,isobutyl etc.) (preferably 1 to 3 C₁₋₆ alkoxy) [preferably thienylgroup, benzo[b]thienyl group, furyl group or pyridyl group, each ofwhich is optionally substituted by 1 to 3 C₁₋₆ alkoxy],particularly preferably (i) a hydrogen atom or (ii) a C₆₋₁₄ aryl group(e.g., phenyl group) optionally substituted by 1 to 5 (preferably 1 to3) halogens atoms (e.g., a fluorine atom, a chlorine atom, a bromineatom, an iodine atom).

R³ and R⁴ are preferably the same or different and each is a hydrogenatom or an optionally substituted hydrocarbon group, an acyl group, ahalogen atom, a cyano group or a nitro group.

Of these, a hydrogen atom, a C₁₋₆ alkyl group (e.g., methyl, ethyl,n-propyl, isobutyl etc.), a C₆₋₁₄ aryl group (e.g., phenyl etc.), a C₁₋₆alkyl-carbonyl group (e.g., acetyl, propionyl, butyryl, isobutyryl,pentanoyl, hexanoyl, heptanoyl etc.), a halogen atom (e.g., a fluorineatom, a chlorine atom, a bromine atom, an iodine atom), a cyano groupand a nitro group are preferable, particularly, a hydrogen atom, a C₁₋₆alkyl group (e.g., methyl, ethyl, n-propyl, isobutyl etc.), a C₁₋₆alkyl-carbonyl group (e.g., acetyl, propionyl, butyryl, isobutyryl,pentanoyl, hexanoyl, heptanoyl etc.), a halogen atom (e.g., a fluorineatom, a chlorine atom, a bromine atom, an iodine atom), a cyano groupand a nitro group are preferable.

In the aforementioned formula (I), R⁵ and R⁶ are the same or differentand each is a hydrogen atom or an optionally substituted hydrocarbongroup.

As the “optionally substituted hydrocarbon group” for R⁵ or R⁶, thegroups similar to the “optionally substituted hydrocarbon group” for theaforementioned R⁴⁰ can be mentioned.

Particularly preferably, R⁵ and R⁶ are each independently a hydrogenatom or a C₁₋₆ alkyl group (e.g., methyl, ethyl, n-propyl, isobutyletc.).

In the aforementioned formula (I⁰), the “optionally substitutedhydrocarbon group” for R²⁸ is the same as the “optionally substitutedhydrocarbon group” for R¹ of the formula (I).

The “optionally substituted hydrocarbon group”, “acyl group” or “halogenatom” for R²⁹, R³⁰ or R³¹ in the aforementioned formula (I⁰) is the sameas the “optionally substituted hydrocarbon group”, “acyl group” or“halogen atom” for R², R³ or R⁴ in the formula (I).

The “optionally substituted hydrocarbon group” for R³² or R³³ in theaforementioned formula (I⁰) is the same as the “optionally substitutedhydrocarbon group” for R⁵ or R⁶ in the formula (I).

The “spacer having 1 to 20 atoms in the main chain” for X⁴ or Y⁴ in theaforementioned formula (I⁰) is the same as the “spacer having 1 to 20atoms in the main chain” for X or Y in the formula (I).

Preferable embodiment of each substituent in the aforementioned formula(I⁰) is according to the preferable embodiment of the substituent in theformula (I).

That is, R²⁸ is preferably an optionally substituted alkyl group, anoptionally substituted aryl group or an optionally substituted aralkylgroup, and an optionally substituted aryl group is particularlypreferable. Of these, a C₆₋₁₄ aryl group (e.g., phenyl etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) substituents selected fromhalogen, hydroxy and C₁₋₆ alkyl is particularly preferable.

As R²⁹, a hydrogen atom or an optionally substituted hydrocarbon groupis preferable, and a hydrogen atom or an optionally substituted arylgroup is particularly preferable.

Of these, a hydrogen atom or a C₆₋₁₄ aryl group (e.g., phenyl group)optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g., afluorine atom, a chlorine atom, a bromine atom, an iodine atom) ispreferable.

R³⁰ and R³¹ are the same or different and each is preferably a hydrogenatom, a C₁₋₆ alkyl group (e.g., methyl, ethyl, n-propyl, isobutyl etc.),a C₁₋₆ alkyl-carbonyl group (e.g., acetyl, propionyl, butyryl,isobutyryl, pentanoyl, hexanoyl, heptanoyl etc.), a halogen atom (e.g.,a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), acyano group or a nitro group.

Preferably, R³² and R³³ are each independently a hydrogen atom or a C₁₋₆alkyl group (e.g., methyl, ethyl, n-propyl, isobutyl etc.).

A preferable embodiment of X⁴ or Y⁴ is the same as the preferableembodiment of X or Y in the aforementioned formula (I).

As X⁴, —SO₂—, —SO₂—N(R⁷)— (R⁷ is as defined above), —N(R⁸)—SO₂—(R⁸ is asdefined above), —N(R⁹)— (R⁹ is as defined above) or —O— is preferable.Particularly, —SO₂— is preferable.

As Y⁴, a bond or C₁₋₈ alkylene (e.g., —CH₂—, —(CH₂)₂—, —(CH₂)₃—,—(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —CHCH₃—, —C(CH₃)₂—, —(CH(CH₃))₂—,—(CH₂)₂C(CH₃)₂—, —(CH₂)₃C(CH₃)₂— and the like) is preferable.

As compound (I), a compound represented by the following formula (II)

wherein X⁵ is —SO₂—, —SO₂—N(R⁷)— (R⁷ is as defined above), —N(R⁸)—SO₂—(R⁸ is as defined above), —N(R⁹)— (R⁹ is as defined above) or —O—,Y⁵ is an optionally substituted alkylene group,R³⁴ is an optionally substituted hydrocarbon group,R³⁵ is a hydrogen atom or an optionally substituted hydrocarbon group,R³⁶ and R³⁷ are each independently a hydrogen atom, an optionallysubstituted hydrocarbon group, an acyl group, a halogen atom, a cyanogroup or a nitro group,R³⁸ and R³⁹ are each independently a hydrogen atom or an optionallysubstituted hydrocarbon group, and R³⁵ and/or R³⁷ are/is not a1,3-dioxaindan-6-yl group] or a salt thereof (hereinafter abbreviated ascompound (II)) is preferable. However,3-[[2,3-dimethyl-1-(4-methylphenyl)sulfonyl]-1H-pyrrol-4-yl]-2-methyl-alaninemethyl ester is excluded.

As an embodiment of preferable substituent for X⁵, a group similar tothe aforementioned X can be mentioned, and —SO₂— is particularlypreferable.

As the “optionally substituted alkylene group” for Y⁵, a group similarto the aforementioned “optionally substituted alkylene group”exemplified for Y can be mentioned. As Y⁵, C₁₋₈ alkylene (e.g., —CH₂—,—(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —CHCH₃—, —C(CH₃)₂—,—(CH(CH₃))₂—, —(CH₂)₂C(CH₃)₂—, —(CH₂)₃C(CH₃)₂— and the like) arepreferable.

As the “optionally substituted hydrocarbon group” for R³⁴, a groupsimilar to the aforementioned “optionally substituted hydrocarbon group”for R⁴⁰ can be mentioned.

As R³⁴, an optionally substituted alkyl group, an optionally substitutedaryl group or an optionally substituted aralkyl group is preferable, andan optionally substituted aryl group is more preferable.

Of these, [1] a C₆₋₁₄ aryl group (e.g., phenyl etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) substituents selected from (1)halogen (e.g., fluorine, chlorine, bromine, iodine), (2) hydroxy, (3)C₁₋₆ alkyl (e.g., methyl, ethyl, n-propyl, isobutyl etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine) and (4) C₁₋₆ alkoxy (e.g., methoxy, ethoxy,n-propoxy, isobutoxy etc.), or [2] a C₁₋₆ alkyl group (e.g., methyl,ethyl, n-propyl, isobutyl etc.) is particularly preferable.

As the “optionally substituted hydrocarbon group” for R³⁵, a groupsimilar to the aforementioned “optionally substituted hydrocarbon group”for R⁴⁰ can be mentioned. However, it is not a 1,3-dioxaindan-6-ylgroup.

As R³⁵, a hydrogen atom or an optionally substituted aryl group(substituent of aryl group is not a —O—CH₂—O— group) is preferable.

Of these, (i) a hydrogen atom, or (ii) a C₆₋₁₄ aryl group (e.g., phenyletc.) optionally substituted by 1 to 5 (preferably 1 to 3) substituentsselected from halogen (e.g., fluorine, chlorine, bromine, iodine) andC₁₋₆ alkyl (e.g., methyl, ethyl, n-propyl, isobutyl etc.) is preferable.

As the “optionally substituted hydrocarbon group” for R³⁶ or R³⁷, agroup similar to the aforementioned “optionally substituted hydrocarbongroup” for R⁴⁰ can be mentioned. However, R³⁷ is not a1,3-dioxaindan-6-yl group.

As the “acyl group” for R³⁶ or R³⁷, a group similar to theaforementioned “acyl group” for R², R³ or R⁴ can be mentioned.

As R³⁶ or R³⁷, a hydrogen atom, a C₁₋₆ alkyl group (e.g., methyl, ethyl,n-propyl, isobutyl etc.), a C₁₋₆ alkyl-carbonyl group (e.g., acetyl,propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl etc.), ahalogen atom (e.g., a fluorine atom, a chlorine atom, a bromine atom, aniodine atom), a cyano group or a nitro group is preferable.

As the “optionally substituted hydrocarbon group” for R³⁸ or R³⁹, agroup similar to the aforementioned “optionally substituted hydrocarbongroup” for R⁴⁰ can be mentioned.

Preferably, R³⁸ and R³⁹ are each independently a hydrogen atom or a C₁₋₆alkyl group (e.g., methyl, ethyl, n-propyl, isobutyl etc.).

In addition, as a preferable embodiment of compound (I), a compoundrepresented by the following formula can be mentioned. A compoundrepresented by

wherein X⁶ is sulfonyl,Y⁶ is a C₁₋₆ alkylene group (e.g., —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—,—(CH₂)₅—, —(CH₂)₆—, —CHCH₃—, —C(CH₃)₂—, —(CH(CH₃))₂—, —(CH₂)₂C(CH₃)₂—,—(CH₂)₃C(CH₃)₂— etc.),R⁴¹ is [1] a C₆₋₁₄ aryl group (e.g., phenyl etc.) optionally substitutedby 1 to 5 (preferably 1 to 3) substituents selected from (1) halogen(e.g., fluorine, chlorine, bromine, iodine), (2) hydroxy, (3) C₁₋₆ alkyl(e.g., methyl, ethyl, n-propyl, isobutyl etc.) optionally substituted by1 to 5 (preferably 1 to 3) halogens (e.g., fluorine, chlorine, bromine,iodine) and (4) C₁₋₆ alkoxy (e.g., methoxy, ethoxy, n-propoxy, isobutoxyetc.) or [2] a C₁₋₆ alkyl group (e.g., methyl, ethyl, n-propyl, isobutyletc.),R⁴² is a hydrogen atom, a C₆₋₁₄ aryl group (e.g., phenyl etc.)optionally substituted by 1 to 5 (preferably 1 to 3) substituentsselected from halogen (e.g., fluorine, chlorine, bromine, iodine) andC₁₋₆ alkyl (e.g., methyl, ethyl, n-propyl, isobutyl etc.),R⁴³ and R⁴⁴ are each independently a hydrogen atom, andR⁴⁵ and R⁴⁶ are each independently a hydrogen atom or a C₁₋₆ alkyl group(e.g., methyl, ethyl, n-propyl, isobutyl etc.) is preferable.

In another embodiment, of the compounds encompassed in compound (I),particularly preferable compounds are the following [a], [b], [c] and[d].

[a] A compound represented by the formula (II-a)

wherein X¹ is —SO₂—, —SO₂—N(R⁷)— (R⁷ is a hydrogen atom or an optionallysubstituted hydrocarbon group), —N(R⁸)—SO₂— (R⁸ is a hydrogen atom or anoptionally substituted hydrocarbon group), —N(R⁹)— (R⁹ is a hydrogenatom or an optionally substituted hydrocarbon group) or —O—,Y¹ is an optionally substituted alkylene group, R¹⁰ is an optionallysubstituted hydrocarbon group or an optionally substituted heterocyclicgroup,R¹¹ is a hydrogen atom, an optionally substituted hydrocarbon group, anoptionally substituted thienyl group, an optionally substitutedbenzo[b]thienyl group, an optionally substituted furyl group, anoptionally substituted pyridyl group, an optionally substitutedpyrazolyl group or an optionally substituted pyrimidinyl group[preferably, a hydrogen atom, an optionally substituted hydrocarbongroup, an optionally substituted thienyl group, an optionallysubstituted benzo[b]thienyl group, an optionally substituted furyl groupor an optionally substituted pyridyl group], R¹² and R¹³ are eachindependently a hydrogen atom, an optionally substituted hydrocarbongroup, an acyl group, a halogen atom, a cyano group or a nitro group(provided that R¹² and R¹³ are not simultaneously hydrogen atoms), andR¹⁴ and R¹⁵ are each independently a hydrogen atom or an optionallysubstituted hydrocarbon group] (provided that3-[[2,3-dimethyl-1-(4-methylphenyl)sulfonyl]-1H-pyrrol-4-yl]-2-methyl-alaninemethyl ester is excluded) or a salt thereof.

The “optionally substituted hydrocarbon group” and “optionallysubstituted heterocyclic group” for R¹⁰ mean the same as the “optionallysubstituted hydrocarbon group” and “optionally substituted heterocyclicgroup” for R¹ in the formula (I).

The “optionally substituted hydrocarbon group”, “optionally substitutedthienyl group”, “optionally substituted benzo[b]thienyl group”,“optionally substituted furyl group”, “optionally substituted pyridylgroup”, “optionally substituted pyrazolyl group” and “optionallysubstituted pyrimidinyl group” for R¹¹ mean the same as the “optionallysubstituted hydrocarbon group”, “optionally substituted thienyl group”,“optionally substituted benzo[b]thienyl group”, “optionally substitutedfuryl group”, “optionally substituted pyridyl group”, “optionallysubstituted pyrazolyl group” and “optionally substituted pyrimidinylgroup” each for R² in the formula (I).

The “optionally substituted hydrocarbon group”, “acyl group” or “halogenatom” for R¹² or R¹³ means the same as the “optionally substitutedhydrocarbon group”, “acyl group” or “halogen atom” for R³ or R⁴ in theformula (I).

The “optionally substituted hydrocarbon group” for R¹⁴ or R¹⁵ means thesame as the “optionally substituted hydrocarbon group” for R⁵ or R⁶ inthe formula (I).

As a preferable embodiment of X¹, a group similar to X in theaforementioned formula (I) can be mentioned.

As the “optionally substituted alkylene group” for Y¹, a group similarto the “optionally substituted alkylene group” for Y in theaforementioned formula (I) can be mentioned.

A preferable embodiment of each substituent in the aforementionedformula (II-a) is similar to the preferable embodiment of thecorresponding substituent in the formula (I).

That is, as R¹⁰, an optionally substituted alkyl group, an optionallysubstituted aryl group, an optionally substituted aralkyl group or anoptionally substituted thienyl group is preferable, an optionallysubstituted alkyl group, optionally substituted aryl group, optionallysubstituted aralkyl group or (unsubstituted) thienyl group is morepreferable, and an optionally substituted aryl group is particularlypreferable.

Specifically,

[1] a C₆₋₁₄ aryl group (e.g., phenyl etc.) optionally substituted by 1to 5 (preferably 1 to 3) substituents selected from (i) halogen (e.g.,fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano, (iv)C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1to 5 (preferably 1 to 3) halogens (e.g., fluorine, chlorine, bromine,iodine), (v) C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine) and (vi) phenyl, or[2] an (unsubstituted) thienyl group,is particularly preferable.

As R¹¹, (i) a hydrogen atom, (ii) an optionally substituted hydrocarbongroup, or (iii) a thienyl group, a benzo[b]thienyl group, a furyl group,a pyridyl group, a pyrazolyl group or a pyrimidinyl group optionallysubstituted by 1 to 3 substituents selected from C₁₋₆ alkoxy (e.g.,methoxy, ethoxy etc.) and C₁₋₆ alkyl (e.g., methyl, ethyl etc.)[particularly, a thienyl group, a benzo[b]thienyl group, a furyl groupor a pyridyl group, which is optionally substituted by 1 to 3 C₁₋₆alkoxy] is preferable.

Of the above-mentioned groups, an optionally substituted hydrocarbongroup is more preferable, and an optionally substituted aryl group isparticularly preferable.

Specifically, as R¹¹,

[1] a hydrogen atom, [2] a C₆₋₁₄ aryl group (e.g., phenyl group,naphthyl group) optionally substituted by 1 to 5 (preferably 1 to 3)substituents selected from (i) a halogen atom (e.g., a fluorine atom, achlorine atom, a bromine atom, an iodine atom), (ii) cyano, (iii) aminooptionally substituted by one or two C₁₋₆ alkyl (e.g., methyl, ethyletc.) or acetyl, (iv) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.)optionally substituted by 1 to 5 (preferably 1 to 3) halogens (e.g.,fluorine, chlorine, bromine, iodine), (v) C₁₋₆ alkoxy (e.g., methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy,hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3)halogens (e.g., fluorine, chlorine, bromine, iodine), (vi) phenoxy,(vii) C₁₋₆ alkylthio (e.g., methylthio, ethylthio etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine), (viii) acetyl and (ix) aminocarbonyl, or [3]a thienyl group, a benzo[b]thienyl group, a furyl group, a pyridylgroup, a pyrazolyl group or a pyrimidinyl group optionally substitutedby 1 to 3 substituents selected from C₁₋₆ alkoxy (e.g., methoxy, ethoxyetc.) and C₁₋₆ alkyl (e.g., methyl, ethyl etc.) [particularly, a thienylgroup, a benzo[b]thienyl group, a furyl group or a pyridyl group, whichis optionally substituted by 1 to 3 C₁₋₆ alkoxy] is preferable, andparticularly, a C₆₋₁₄ aryl group (e.g., phenyl group) optionallysubstituted by 1 to 5 (preferably 1 to 3) substituents selected from (i)a halogen atom and (ii) C₁₋₆ alkyl optionally substituted by 1-5(preferably 1-3) halogens is preferable.

R¹² and R¹³ are the same or different and each is preferably a hydrogenatom, a C₁₋₆ alkyl group (e.g., methyl, ethyl, n-propyl, isobutyl etc.),a C₆₋₁₄ aryl group (e.g., phenyl etc.), a C₁₋₆ alkyl-carbonyl group(e.g., acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl,heptanoyl etc.), a halogen atom (e.g., a fluorine atom, a chlorine atom,a bromine atom, an iodine atom), a cyano group or a nitro group.However, R¹² and R¹³ are not simultaneously hydrogen atoms.

R¹² is preferably a hydrogen atom, a C₁₋₆ alkyl group (e.g., methyl,ethyl, n-propyl, isobutyl etc.) or a C₆₋₁₄ aryl group (e.g., phenyletc.).

R¹³ is preferably a hydrogen atom or a C₁₋₆ alkyl group (e.g., methyl,ethyl, n-propyl, isobutyl etc.).

Preferably, R¹⁴ and R¹⁵ are each independently a hydrogen atom or a C₁₋₆alkyl group (e.g., methyl, ethyl, n-propyl, isobutyl etc.).

As a preferable embodiment of X¹ or Y¹, the preferable embodiment of Xor Y in the aforementioned formula (I) can be mentioned.

As X¹, —SO₂— is particularly preferable.

As Y¹, C₁₋₈ alkylene (e.g., —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—,—(CH₂)₅—, —(CH₂)₆—, —CHCH₃—, —C(CH₃)₂—, —(CH(CH₃))₂—, —(CH₂)₂C(CH₃)₂—,—(CH₂)₃C(CH₃)₂— and the like) is preferable.

[b] A compound represented by the formula (II-b)

wherein X² is —SO₂—N(R⁷)— (R⁷ is a hydrogen atom or an optionallysubstituted hydrocarbon group), —N(R⁸)—SO₂— (R⁸ is a hydrogen atom or anoptionally substituted hydrocarbon group), —N(R⁹)— (R⁹ is a hydrogenatom or an optionally substituted hydrocarbon group) or —O—,Y² is an optionally substituted alkylene group,R¹⁶ is an optionally substituted hydrocarbon group or an optionallysubstituted heterocyclic group,R¹⁷ is a hydrogen atom, an optionally substituted hydrocarbon group, anoptionally substituted thienyl group, an optionally substitutedbenzo[b]thienyl group, an optionally substituted furyl group, anoptionally substituted pyridyl group, an optionally substitutedpyrazolyl group or an optionally substituted pyrimidinyl group,R¹⁸ and R¹⁹ are each independently a hydrogen atom,R²⁰ and R²¹ are each independently a hydrogen atom or an optionallysubstituted hydrocarbon group, and R¹⁷ is not a 1,3-dioxaindan-6-ylgroup, or a salt thereof.

The “optionally substituted hydrocarbon group” and “optionallysubstituted heterocyclic group” for R¹⁶ mean the same as the “optionallysubstituted hydrocarbon group” and “optionally substituted heterocyclicgroup” for R¹ in the formula (I).

The “optionally substituted hydrocarbon group”, “optionally substitutedthienyl group”, “optionally substituted benzo[b]thienyl group”,“optionally substituted furyl group”, “optionally substituted pyridylgroup”, “optionally substituted pyrazolyl group” or “optionallysubstituted pyrimidinyl group” for R¹⁷ means the same as the “optionallysubstituted hydrocarbon group”, “optionally substituted thienyl group”,“optionally substituted benzo[b]thienyl group”, “optionally substitutedfuryl group”, “optionally substituted pyridyl group”, “optionallysubstituted pyrazolyl group” or “optionally substituted pyrimidinylgroup” for R² in the formula (I).

The “optionally substituted hydrocarbon group” for R²⁰ or R²¹ means thesame as the “optionally substituted hydrocarbon group” for R⁵ or R⁶ inthe formula (I).

As a preferable embodiment of X², a group similar to X in theaforementioned formula (I) can be mentioned.

As the “optionally substituted alkylene group” for Y², a group similarto the “optionally substituted alkylene group” for Y in theaforementioned formula (I) can be mentioned.

A preferable embodiment of each substituent in the aforementionedformula (II-b) is similar to the preferable embodiment of thecorresponding substituent in the formula (I).

That is, as R¹⁶, an optionally substituted alkyl group, an optionallysubstituted aryl group, an optionally substituted aralkyl group or anoptionally substituted thienyl group is preferable, an optionallysubstituted alkyl group, an optionally substituted aryl group, anoptionally substituted aralkyl group or an (unsubstituted) thienyl groupis more preferable, and an optionally substituted aryl group isparticularly preferable.

Specifically,

[1] a C₆₋₁₄ aryl group (e.g., phenyl etc.) optionally substituted by 1to 5 (preferably 1 to 3) substituents selected from (i) halogen (e.g.,fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano, (iv)C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1to 5 (preferably 1 to 3) halogens (e.g., fluorine, chlorine, bromine,iodine), (v) C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine) and (vi) phenyl, or[2] an (unsubstituted) thienyl group,is particularly preferable.

As R¹⁷, (i) a hydrogen atom, (ii) an optionally substituted hydrocarbongroup, or (iii) a thienyl group, a benzo[b]thienyl group, a furyl group,a pyridyl group, a pyrazolyl group or a pyrimidinyl group optionallysubstituted by 1 to 3 substituents selected from C₁₋₆ alkoxy (e.g.,methoxy, ethoxy etc.) and C₁₋₆ alkyl (e.g., methyl, ethyl etc.)[particularly, a thienyl group, a benzo[b]thienyl group, a furyl groupor a pyridyl group, which is optionally substituted by 1 to 3 C₁₋₆alkoxy] is preferable, and of those mentioned above, an optionallysubstituted hydrocarbon group is more preferable, and an optionallysubstituted aryl group is particularly preferable.

Specifically, as R¹⁷,

[1] a hydrogen atom, [2] a C₆₋₁₄ aryl group (e.g., phenyl group)optionally substituted by 1 to 5 (preferably 1 to 3) substituentsselected from (i) a halogen atom (e.g., a fluorine atom, a chlorineatom, a bromine atom, an iodine atom), (ii) cyano, (iii) aminooptionally substituted by one or two C₁₋₆ alkyl (e.g., methyl, ethyletc.) or acetyl, (iv) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.)optionally substituted by 1 to 5 (preferably 1 to 3) halogens (e.g.,fluorine, chlorine, bromine, iodine), (v) C₁₋₆ alkoxy (e.g., methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy,hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3)halogens (e.g., fluorine, chlorine, bromine, iodine), (vi) phenoxy,(vii) C₁₋₆ alkylthio (e.g., methylthio, ethylthio etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine), (viii) acetyl and (ix) aminocarbonyl, or [3]a thienyl group, a benzo[b]thienyl group, a furyl group, a pyridylgroup, a pyrazolyl group or a pyrimidinyl group optionally substitutedby 1 to 3 substituents selected from C₁₋₆ alkoxy (e.g., methoxy, ethoxyetc.) and C₁₋₆ alkyl (e.g., methyl, ethyl etc.) [particularly, a thienylgroup, a benzo[b]thienyl group, a furyl group or a pyridyl group, whichis optionally substituted by 1 to 3 C₁₋₆ alkoxy]is preferable, and particularly, a C₆₋₁₄ aryl group (e.g., a phenylgroup) optionally substituted by 1 to 5 (preferably 1 to 3) substituentsselected from (i) a halogen atom and (ii) C₁₋₆ alkyl optionallysubstituted by 1-5 (preferably 1-3) halogens is preferable.

Preferably, R²⁰ and R²¹ are each independently a hydrogen atom or a C₁₋₆alkyl group (e.g., methyl, ethyl, n-propyl, isobutyl etc.).

As a preferable embodiment of Y², the preferable embodiment of Y in theaforementioned formula (I) can be mentioned, and C₁₋₈ alkylene (e.g.,—CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —CHCH₃—,—C(CH₃)₂—, —(CH(CH₃))₂—, —(CH₂)₂C(CH₃)₂—, —(CH₂)₃C(CH₃)₂— and the like)is preferable.

[c] A compound represented by the formula (II-c)

wherein X³ is —SO₂—,Y³ is a methylene group (—CH₂—),R²² is an alkyl group, an optionally substituted phenyl group or anoptionally substituted thienyl group,R²³ is an optionally substituted C₆₋₁₄ aryl group, an optionallysubstituted thienyl group, an optionally substituted benzo[b]thienylgroup, an optionally substituted furyl group, an optionally substitutedpyridyl group, an optionally substituted pyrazolyl group or anoptionally substituted pyrimidinyl group,R²⁴ and R²⁵ are each individually a hydrogen atom,R²⁶ is a hydrogen atom or a methyl group, andR²⁷ is a methyl group, or a salt thereof.

As the “alkyl group” for R²², for example, C₁₋₆ alkyl (e.g., methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, hexyl etc.) and the like can be mentioned.

As the substituent of the “phenyl group” for R²², those similar to thesubstituents of the “aryl” exemplified as the aforementioned“hydrocarbon group” of the “optionally substituted hydrocarbon group”for R⁴⁰ can be mentioned. The number of the substituents is 1-5(preferably 1-3).

As the substituent of the “phenyl group”, (i) halogen (e.g., fluorine,chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano, (iv) C₁₋₆ alkyl(e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5(preferably 1 to 3) halogens (e.g., fluorine, chlorine, bromine,iodine), (v) C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine), (vi) phenyl and the like are preferable.

As the “thienyl group” for R²², 2- or 3-thienyl can be mentioned.

As the substituent of the thienyl group, those similar to thesubstituents of the cycloalkyl, aryl or aralkyl exemplified as theaforementioned “hydrocarbon group” for R⁴⁰ can be mentioned. The numberof the substituents is 1-3.

As the C₆₋₁₄ aryl group of the “optionally substituted C₆₋₁₄ aryl group”for R²³, phenyl and naphthyl can be mentioned. Particularly, phenyl ispreferable.

As the substituent of the “C₆₋₁₄ aryl group” for R²³, those similar tothe substituents of the “aryl” exemplified as the aforementioned“hydrocarbon group” of the “optionally substituted hydrocarbon group”for R⁴⁰ can be mentioned. The number of the substituents is 1-5(preferably 1-3).

As the substituent of the “C₆₋₁₄ aryl group”, (i) a halogen atom (e.g.,a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), (ii)cyano, (iii) amino optionally substituted by one or two C₁₋₆ alkyl(e.g., methyl, ethyl etc.) or acetyl, (iv) C₁₋₆ alkyl (e.g., methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3)halogens (e.g., fluorine, chlorine, bromine, iodine), (v) C₁₋₆alkoxy(e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5(preferably 1 to 3) halogens (e.g., fluorine, chlorine, bromine,iodine), (vi) phenoxy, (vii) C₁₋₆ alkylthio (e.g., methylthio, ethylthioetc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogens(e.g., fluorine, chlorine, bromine, iodine), (viii) acetyl, (ix)aminocarbonyl and the like are preferable.

As the “optionally substituted thienyl group” for R²³, those similar tothe above-mentioned “optionally substituted thienyl group” for R²² canbe mentioned.

As the “benzo[b]thienyl group” of the “optionally substitutedbenzo[b]thienyl group” for R²³, 2- or 3-benzo[b]thienyl can bementioned.

As the substituent of the benzo[b]thienyl group, those similar to thesubstituents of the cycloalkyl, aryl or aralkyl exemplified as theaforementioned “hydrocarbon group” for R⁴⁰ can be mentioned. The numberof the substituents is 1 to 5, preferably 1 to 3.

As the “furyl group” of the “optionally substituted furyl group” forR²³, 2- or 3-furyl can be mentioned.

As the “substituent” of the furyl group, those similar to thesubstituents of the cycloalkyl, aryl or aralkyl exemplified as theaforementioned “hydrocarbon group” for R⁴⁰ can be mentioned. The numberof the substituents is 1 to 3.

As the “pyridyl group” of the “optionally substituted pyridyl group” forR²³, 2-, 3- or 4-pyridyl can be mentioned.

As the “substituent” of the pyridyl group, those similar to thesubstituents of the cycloalkyl, aryl or aralkyl exemplified as theaforementioned “hydrocarbon group” for R⁴⁰ can be mentioned. The numberof the substituents is 1 to 3.

As the “pyrazolyl group” of the “optionally substituted pyrazolyl group”for R²³, 3- or 4-pyrazolyl can be mentioned.

As the “substituent” of the pyrazolyl group, those similar to thesubstituents of the cycloalkyl, aryl or aralkyl exemplified as theaforementioned “hydrocarbon group” for R⁴⁰ can be mentioned. The numberof the substituents is 1 to 3.

As the “pyrimidinyl group” of the “optionally substituted pyrazolylgroup” for R²³, 2-, 4- or 5-pyrimidinyl can be mentioned.

As the substituent of the “pyrimidinyl group”, those similar to thesubstituents of the “cycloalkyl, aryl or aralkyl” exemplified as theaforementioned “hydrocarbon group” for R⁴⁰ can be mentioned. The numberof the substituents is 1 to 3.

As the substituent of the above-mentioned thienyl group, benzo[b]thienylgroup, furyl group, pyridyl group, pyrazolyl group, pyrimidinyl group,C₁₋₆ alkoxy (e.g., methoxy, ethoxy etc.) and C₁₋₆ alkyl (e.g., methyl,ethyl, n-propyl, isobutyl etc.) and the like are preferable, and C₁₋₆alkoxy (e.g., methoxy, ethoxy etc.) is particularly preferable. Thenumber of the substituents is 1 to 3.

As R²²,

[1] a C₆₋₁₄ aryl group (e.g., phenyl etc.) optionally substituted by 1to 5 (preferably 1 to 3) substituents selected from (i) halogen (e.g.,fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano, (iv)C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1to 5 (preferably 1 to 3) halogens (e.g., fluorine, chlorine, bromine,iodine), (v) C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine) and (vi) phenyl, or[2] an (unsubstituted) thienyl group,is particularly preferable.

As R²³, [1] a phenyl group optionally substituted by 1 to 5 (preferably1 to 3) substituents selected from (i) a halogen atom (e.g., a fluorineatom, a chlorine atom, a bromine atom, an iodine atom), (ii) cyano,(iii) amino optionally substituted by one or two C₁₋₆ alkyl (e.g.,methyl, ethyl etc.) or acetyl, (iv) C₁₋₆ alkyl (e.g., methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyletc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogens(e.g., fluorine, chlorine, bromine, iodine), (v) C₁₋₆ alkoxy (e.g.,methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1to 3) halogens (e.g., fluorine, chlorine, bromine, iodine), (vi)phenoxy, (vii) C₁₋₆ alkylthio (e.g., methylthio, ethylthio etc.)optionally substituted by 1 to 5 (preferably 1 to 3) halogens (e.g.,fluorine, chlorine, bromine, iodine), (viii) acetyl and (ix)aminocarbonyl,

[2] a naphthyl group, or [3] a thienyl group, a benzo[b]thienyl group, afuryl group, a pyridyl group, a pyrazolyl group or a pyrimidinyl groupoptionally substituted by 1 to 3 substituents (preferably 1 to 3 C₁₋₆alkoxy) selected from C₁₋₆ alkoxy (e.g., methoxy, ethoxy etc.) and C₁₋₆alkyl (e.g., methyl, ethyl, n-propyl, isobutyl etc.), [particularly, athienyl group, a benzo[b]thienyl group, a furyl group or a pyridylgroup, which is optionally substituted by 1 to 3 C₁₋₆ alkoxy]is preferable.

[d] A compound represented by the formula (II-d)

wherein R¹⁰¹ is a monocyclic nitrogen-containing heterocyclic groupoptionally condensed with a benzene ring or heterocycle, the monocyclicnitrogen-containing heterocyclic group optionally condensed with thebenzene ring or heterocycle may have a substituent, R¹⁰² is anoptionally substituted C₆₋₁₄ aryl group or an optionally substitutedthienyl group, R¹⁰³ and R¹⁰⁴ are each a hydrogen atom, or one of R¹⁰³and R¹⁰⁴ is a hydrogen atom and the other is an optionally substitutedlower alkyl group, acyl group, halogen atom, cyano group or nitro group,and R¹⁰⁵ is an alkyl group, or a salt thereof.

In the formula (II-d), as the “nitrogen-containing monocyclicheterocyclic group optionally condensed with a benzene ring or aheterocycle” for R¹⁰¹,

(1) a nitrogen-containing monocyclic heterocyclic group, and(2) a fused ring group represented by the formula:

wherein ring A is a nitrogen-containing monocyclic heterocyclic group,ring B is a benzene ring or a heterocycle, a and b are each a bridgeheadring-constituting atom (e.g., a carbon atom, a nitrogen atom and thelike), ═ and shows a single bond or a double bond, provided that a bondto an —SO₂— group in the formula (II-d) is present in a ringA-constituting atom (ring atom) other than the bridgeheadring-constituting atoms a and b, can be mentioned.

As used herein, ring A needs only to contain, as a ring A-constitutingatom (ring atom), at least one (preferably 1 to 4, more preferably 1 or2) nitrogen atom, and one or both of the bridgehead ring-constitutingatoms a and b may be nitrogen atoms.

The “nitrogen-containing monocyclic heterocyclic group optionallycondensed with a benzene ring or a heterocycle” optionally hassubstituent(s), and the substituent(s) may be present in any of ring Aand ring B.

As the “nitrogen-containing monocyclic heterocyclic group” of the“nitrogen-containing monocyclic heterocyclic group optionally condensedwith a benzene ring or a heterocycle” and the above-mentioned ring A,for example, an aromatic nitrogen-containing monocyclic heterocyclicgroup, a saturated or unsaturated non-aromatic nitrogen-containingmonocyclic heterocyclic group (aliphatic nitrogen-containing monocyclicheterocyclic group) and the like containing, as a ring-constituting atom(ring atom), at least one (preferably 1 to 4, more preferably 1 or 2)nitrogen atom can be mentioned.

As the “aromatic nitrogen-containing monocyclic heterocyclic group”, forexample, aromatic nitrogen-containing monocyclic heterocyclic groupssuch as pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl (1H-imidazol-1-yl, 1H-imidazol-4-yl etc.), pyrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl (1,2,4-triazol-1-yl, 1,2,4-triazol-4-yletc.), tetrazolyl, pyridyl (2-, 3- or 4-pyridyl etc.), pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl and the like, and N-oxide formsthereof and the like can be mentioned. Of these, a 5- or 6-memberedaromatic nitrogen-containing monocyclic heterocyclic group ispreferable, and thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyland pyridazinyl are preferable, and pyridyl is particularly preferable.

As the “saturated or unsaturated non-aromatic nitrogen-containingmonocyclic heterocyclic group”, partially reduced forms (e.g.,imidazolinyl, tetrahydropyrimidinyl and the like) of the above-mentioned“aromatic nitrogen-containing monocyclic heterocyclic group” and, forexample, azetidinyl, pyrrolidinyl, piperidyl (2-, 3- or 4-piperidyl),morpholinyl, thiomorpholinyl, piperazinyl (1-piperazinyl etc.),homopiperazinyl and the like can be mentioned. Of these, a 5- or6-membered non-aromatic nitrogen-containing monocyclic heterocyclicgroup is preferable.

As the “heterocycle” optionally condensed with a nitrogen-containingmonocyclic heterocyclic group, for example, an aromatic heterocycle ornon-aromatic heterocycle can be mentioned.

As the “aromatic heterocycle”, for example, 5- or 6-membered aromaticmonocyclic heterocycle such as a furan ring, a thiophene ring, a pyrrolering, an oxazole ring, an isoxazole ring, a thiazole ring, anisothiazole ring, an imidazole ring, a pyrazole ring, a 1,2,3-oxadiazolering, a 1,2,4-oxadiazole ring, a 1,3,4-oxadiazole ring, a furazan ring,a 1,2,3-thiadiazole ring, a 1,2,4-thiadiazole ring, a 1,3,4-thiadiazolering, a 1,2,3-triazole ring, a 1,2,4-triazole ring, tetrazole ring,pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazinering and the like and, for example, 8- to 12-membered aromatic fusedheterocycles such as a benzofuran ring, an isobenzofuran ring, abenzo[b]thiophene ring, an indole ring, an isoindole ring, a 1H-indazolering, a benzindazole ring, a benzoxazole ring, a 1,2-benzoisoxazolering, a benzothiazole ring, a benzopyran ring, a 1,2-benzoisothiazolering, a 1H-benzotriazole ring, a quinoline ring, an isoquinoline ring, acinnoline ring, a quinazoline ring, a quinoxaline ring, a phthalazinering, a naphthyridine ring, a purine ring, a pteridine ring, a carbazolering, an α-carboline ring, a β-carboline ring, a γ-carboline ring, anacridine ring, a phenoxazine ring, a phenothiazine ring, a phenazinering, a phenoxathiine ring, a thianthrene ring, a phenanthridine ring, aphenanthrone ring, an indolizine ring, a pyrrolo[1,2-b]pyridazine ring,a pyrazolo[1,5-a]pyridine ring, an imidazo[1,2-a]pyridine ring, animidazo[1,5-a]pyridine ring, an imidazo[1,2-b]pyridazine ring, animidazo[1,2-a]pyrimidine ring, a 1,2,4-triazolo[4,3-a]pyridine ring, a1,2,4-triazolo[4,3-b]pyridazine ring and the like (preferably, aheterocycle wherein the aforementioned 5- or 6-membered aromaticmonocyclic heterocycle is condensed with a benzene ring or a heterocyclewherein the same or different two heterocycles of the aforementioned 5-or 6-membered aromatic monocyclic heterocycle are condensed, morepreferably a heterocycle wherein the aforementioned 5- or 6-memberedaromatic monocyclic heterocyclic group is condensed with a benzene ring,preferably imidazopyrimidinyl etc.) and the like can be mentioned.

As the “non-aromatic heterocycle”, for example, 3- to 8-memberedsaturated or unsaturated non-aromatic heterocycles such as an oxiranering, an azetidine ring, an oxetane ring, a thietane ring, a pyrrolidinering, a tetrahydrofuran ring, a thioran ring, a piperidine ring, atetrahydropyran ring, a morpholine ring, a thiomorpholine ring, apiperazine ring, a 3-hexahydrocyclopenta[c]pyrrole ring, ahomopiperidine ring, a homopiperazine ring and the like, or non-aromaticheterocycles wherein the double bonds of the aforementioned aromaticmonocyclic heterocycle or aromatic fused heterocycle are partly orentirely saturated such as a dihydropyridine ring, a dihydropyrimidinering, a 1,2,3,4-tetrahydroquinoline ring, a1,2,3,4-tetrahydroisoquinoline ring and the like, and the like can bementioned.

As preferable nitrogen-containing monocyclic heterocyclic groupcondensed with a benzene ring or a heterocycle, for example,nitrogen-containing aromatic fused heterocyclic groups such as 8- to16-membered (preferably 8- to 12-membered) nitrogen-containing aromaticbicyclic fused heterocyclic groups such as 2- or 3-indolyl, 1- or3-isoindolyl, 1H-indazol-3-yl, 2-benzimidazolyl, 2-benzoxazolyl,3-benzoisoxazolyl, 2-benzothiazolyl, 3-benzoisothiazolyl, 2-, 3- or4-quinolyl, 1-, 3- or 4-isoquinolyl, 3- or 4-cinnolinyl, 2- or4-quinazolinyl, 2- or 3-quinoxalinyl, 1- or 4-phthalazinyl,naphthyridinyl, purinyl, pteridinyl, 1,7-phenanthrolin-2-, 3- or 4-yl,1-, 2- or 3-indolizinyl, pyrrolo[1,2-b]pyridazinyl,pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,2-b]pyrazolyl,imidazo[1,5-a]pyridyl, imidazo[4,5-c]pyridyl,pyrazolo[1,5-a]pyrimidinyl, pyrazolo[1,5-c]pyrimidinyl,pyrazolo[3,4-d]pyrimidinyl, imidazo[1,2-b]pyridazinyl,imidazo[1,5-b]pyridazinyl, pyrazolo[3,4-b]pyridyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl,1,2,4-triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,2-a]pyridazinyl,[1,2,3]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-c]pyrimidinyl,[1,2,4]triazolo[1,5-a]pyridyl, [1,2,4]triazolo[4,3-a]pyridyl,pyrazolo[5,1-b]thiazolyl, pyrrolo[2,1-f][1,2,4]triazinyl,pyrrolo[1,2-b]pyridazinyl, pyrrolo[2,3-d]pyrimidinyl,pyrrolo[2,3-b]pyridyl, thieno[3,2-b]pyrimidinyl, thieno[2,3-b]pyridyl,thieno[2,3-c]pyridyl, thieno[3,2-b]pyridyl, thieno[3,2-c]pyridyl,pyrido[2,3-b]pyrazyl, pyrido[3,4-b]pyrazyl, pyrido[2,3-d]pyrimidinyl,pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl and the like, and thelike, and the like can be mentioned. As the nitrogen-containing aromaticfused heterocycle, fused pyridine wherein a pyridine ring is condensedwith one or two (preferably one) of the aforementioned 5- or 6-memberednitrogen-containing aromatic monocyclic heterocycles or one or two(preferably one) benzene rings (when condensed with a benzene ring, thepyridine ring has a bond), fused pyrimidine wherein a pyrimidine ring iscondensed with one or two (preferably one) of the aforementioned 5 or6-membered heterocycles, or one or two (preferably one) benzene rings(when condensed with a benzene ring, the pyrimidine ring has a bond) andthe like are preferable.

As the “non-aromatic nitrogen-containing heterocycle”, for example, 3-to 8-membered (preferably 5- or 6-membered) nitrogen-containingsaturated or unsaturated (preferably saturated) non-aromatic heterocycle(aliphatic nitrogen-containing heterocycle) such as azetidine,pyrrolidine, imidazolidine, thiazolidine, oxazolidine, piperidine,morpholine, thiomorpholine, piperazine and the like, ornitrogen-containing non-aromatic heterocycle wherein the double bonds ofthe aforementioned nitrogen-containing aromatic monocyclic heterocycleor nitrogen-containing aromatic fused heterocycle are partly or entirelysaturated, such as 1,2,3,4-tetrahydroquinoline,1,2,3,4-tetrahydroisoquinoline and the like, and the like can bementioned.

As the “nitrogen-containing monocyclic heterocyclic group optionallycondensed with a benzene ring or a heterocycle”, a 5- or 6-memberedaromatic nitrogen-containing monocyclic heterocyclic group is preferablefrom among those mentioned above. Of them, a 6-membered aromaticnitrogen-containing heterocyclic group such as pyridyl (e.g., 2-, 3- or4-pyridyl etc.), pyrimidinyl (e.g., 2-, 4- or 5-pyrimidinyl etc.),pyridazinyl (e.g., 3- or 4-pyridazinyl etc.) and the like is preferable,and pyridyl is particularly preferable.

As the substituent that the “nitrogen-containing monocyclic heterocyclicgroup optionally condensed with a benzene ring or a heterocycle” mayhave, those similar to the substituents of the cycloalkyl, aryl oraralkyl exemplified as the aforementioned “hydrocarbon group” for R⁴⁰can be mentioned. The position of the substituent is not particularlylimited as long as it is a substitutable position, and the number of thesubstituents is, for example, 1 to 5, preferably 1 to 3.

As the “C₆₋₁₄ aryl group” of the “optionally substituted C₆₋₁₄ arylgroup” for R¹⁰², for example, phenyl, 1-naphthyl, 2-naphthyl,2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like can bementioned.

As the substituent that the “C₆₋₁₄ aryl group” optionally has, groupssimilar to the substituents that the “nitrogen-containing monocyclicheterocyclic group optionally condensed with a benzene ring or aheterocycle” for the aforementioned R¹⁰¹ optionally has can bementioned. The number of the substituents is 1 to 5, preferably 1 to 3.

As the “thienyl group” of the “optionally substituted thienyl group” forR¹⁰², 2- or 3-thienyl can be mentioned.

As the substituent that the “thienyl group” optionally has, groupssimilar to the substituents that the “nitrogen-containing monocyclicheterocyclic group optionally condensed with a benzene ring or aheterocycle” for the aforementioned R¹⁰¹ optionally has can bementioned. The number of the substituents is 1 to 4, preferably 1 to 3.

As the “lower alkyl group” of the “optionally substituted lower alkylgroup” for R¹⁰³ or R¹⁰⁴, for example, C₁₋₄ alkyl groups such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and thelike, and the like can be mentioned.

As the substituent that the “lower alkyl group” optionally has, thosesimilar to the substituents of the alkyl, alkenyl or alkynyl exemplifiedas the aforementioned “hydrocarbon group” for R⁴⁰ can be mentioned. Thenumber of the substituents is 1 to 3.

As the “acyl group” for R¹⁰³ or R¹⁰⁴, a group similar to theabove-mentioned “acyl group” for R², R³ or R⁴ can be mentioned.

As the “halogen atom” for R¹⁰³ or R¹⁰⁴, fluorine, chlorine, bromine andiodine can be mentioned.

As the “alkyl group” for R¹⁰⁵, for example, C₁₋₆ alkyl (e.g., methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, hexyl etc.) and the like can be mentioned.

As R¹⁰¹, a “nitrogen-containing monocyclic heterocyclic group optionallycondensed with a benzene ring or a heterocycle” (e.g., 5-6-memberedaromatic nitrogen-containing monocyclic heterocyclic groups such asthiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl andthe like, and the like) optionally substituted by 1 to 3 substituentsselected from (i) halogen (e.g., fluorine, chlorine, bromine, iodine),(ii) hydroxy, (iii) cyano, (iv) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.)optionally substituted by 1 to 5 (preferably 1 to 3) halogens (e.g.,fluorine, chlorine, bromine, iodine), (v) C₁₋₆ alkoxy (e.g., methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy,hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3)halogens (e.g., fluorine, chlorine, bromine, iodine), (vi) amino groupoptionally substituted by C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.)and (vii) oxo is preferable.

Of these, a 6-membered nitrogen-containing aromatic heterocyclic group(e.g., pyridyl groups (e.g., 2-, 3- or 4-pyridyl etc.), pyrimidinylgroups (e.g., 2-, 4- or 5-pyrimidinyl etc.), pyridazinyl groups (e.g.,3- or 4-pyridazinyl etc.) etc.) optionally substituted by 1 to 3substituents selected from (i) halogen (e.g., fluorine, chlorine,bromine, iodine), (ii) hydroxy, (iii) cyano, (iv) C₁₋₆ alkyl (e.g.,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5(preferably 1 to 3) halogens (e.g., fluorine, chlorine, bromine,iodine), (v) C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine) and (vi) an amino group optionallysubstituted by C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) ispreferable, and a pyridyl group optionally substituted by 1 to 3substituents selected from (i) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.)optionally substituted by 1 to 5 (preferably 1 to 3) halogens (e.g.,fluorine, chlorine, bromine, iodine) and (ii) C₁₋₆ alkoxy (e.g.,methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1to 3) halogens (e.g., fluorine, chlorine, bromine, iodine) isparticularly preferable.

As R¹⁰², [1] a C₆₋₁₄ aryl group (e.g., phenyl group) optionallysubstituted by 1 to 5 (preferably 1 to 3) substituents selected from (i)a halogen atom (e.g., a fluorine atom, a chlorine atom, a bromine atom,an iodine atom), (ii) cyano, (iii) C₁₋₆ alkyl (e.g., methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyletc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogens(e.g., fluorine, chlorine, bromine, iodine), (iv) C₁₋₆ alkoxy (e.g.,methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1to 3) halogens (e.g., fluorine, chlorine, bromine, iodine) and (v)acetyl, or

[2] a thienyl group optionally substituted by 1 to 3 substituentsselected from (i) a halogen atom (e.g., a fluorine atom, a chlorineatom, a bromine atom, an iodine atom), (ii) cyano, (iii) C₁₋₆ alkyl(e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5(preferably 1 to 3) halogens (e.g., fluorine, chlorine, bromine,iodine), (iv) C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine) and (v) acetyl, andparticularly, [1] a phenyl group optionally substituted by 1 to 5(preferably 1 to 3) substituents selected from (i) a halogen atom (e.g.,a fluorine atom, a chlorine atom, a bromine atom, an iodine atom) and(ii) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine), or

[2] a thienyl group optionally substituted by 1 to 3 substituentsselected from (i) a halogen atom (e.g., a fluorine atom, a chlorineatom, a bromine atom, an iodine atom) and (ii) C₁₋₆ alkyl (e.g., methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3)halogens (e.g., fluorine, chlorine, bromine, iodine) is preferable.

As R¹⁰², a phenyl group, a 2-fluorophenyl group or a 2-methylphenylgroup is particularly preferable.

Preferably, R¹⁰³ and R¹⁰⁴ are each a hydrogen atom, or one of R¹⁰³ andR¹⁰⁴ is a hydrogen atom and the other is a C₁₋₆ alkyl group (e.g.,methyl, ethyl, n-propyl, isobutyl etc.), a C₁₋₆ alkyl-carbonyl group(e.g., acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl,heptanoyl etc.), a halogen atom (e.g., a fluorine atom, a chlorine atom,a bromine atom, an iodine atom), a cyano group or a nitro group. Acompound wherein both R¹⁰³ and R¹⁰⁴ are hydrogen atoms is particularlypreferable.

As R¹⁰⁵, methyl or ethyl is preferable, and methyl is particularlypreferable.

Of the compounds represented by the formula (II-d), a particularlypreferable compound is, for example,

a compound wherein, for example,R¹⁰¹ is a pyridyl group optionally substituted by 1 to 3 substituentsselected from (i) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine) and (ii) C₁₋₆ alkoxy (e.g., methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxyetc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogens(e.g., fluorine, chlorine, bromine, iodine),R¹⁰² is [1] a phenyl group optionally substituted by 1 to 5 (preferably1 to 3) substituents selected from (i) a halogen atom (e.g., a fluorineatom, a chlorine atom, a bromine atom, an iodine atom) and (ii) C₁₋₆alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1to 5 (preferably 1 to 3) halogens (e.g., fluorine, chlorine, bromine,iodine), or[2] a thienyl group optionally substituted by 1 to 3 substituentsselected from (i) a halogen atom (e.g., a fluorine atom, a chlorineatom, a bromine atom, an iodine atom) and (ii) C₁₋₆ alkyl (e.g., methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3)halogens (e.g., fluorine, chlorine, bromine, iodine),R³ and R⁴ are each a hydrogen atom, and R⁵ is methyl.

As compound (I),

-   N-methyl-1-[1-(phenylsulfonyl)-5-(3-thienyl)-1H-pyrrol-3-yl]methanamine,-   N-methyl-1-[5-phenyl-1-(3-thienylsulfonyl)-1H-pyrrol-3-yl]methanamine,-   N-methyl-1-(1-{[3-(methylsulfonyl)phenyl]sulfonyl}-5-phenyl-1H-pyrrol-3-yl)methanamine,-   1-[1-(1-benzothien-2-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]-N-methylmethanamine,-   1-[5-(2-fluorophenyl)-1-{[3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanamine,-   1-{5-(2-fluorophenyl)-1-[(2-fluorophenyl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine,-   N-methyl-3-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzamide,    or a salt thereof is particularly preferable, and especially, as a    compound represented by the formula (II-d),    N-methyl-1-[5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanamine,    1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine,    N-methyl-1-[4-methyl-1-(pyridin-3-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]methanamine,    N-methyl-1-[1-(pyridin-3-ylsulfonyl)-5-(3-thienyl)-1H-pyrrol-3-yl]methanamine,    N-methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanamine,    1-[5-(2,4-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine,    or a salt thereof is particularly preferable.

As a salt of compound (I), metal salt, ammonium salt, salts with organicbases, salts with inorganic acids, salts with organic acids, salts withbasic or acidic amino acids and the like can be mentioned. Preferableexamples of metal salt include alkali metal salts such as sodium salt,potassium salt and the like; alkaline earth metal salts such as calciumsalt, magnesium salt, barium salt and the like; aluminum salt and thelike. Preferable examples of the salt with organic base include a saltwith trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine,ethanolamine, diethanolamine, triethanolamine, cyclohexylamine,dicyclohexylamine, N,N′-dibenzylethylenediamine and the like. Preferableexamples of the salt with inorganic acid include a salt withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid and the like. Preferable examples of the salt withorganic acid include a salt with formic acid, acetic acid,trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaricacid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid andthe like. Preferable examples of the salt with basic amino acid includea salt with arginine, lysin, ornithine and the like. Preferable examplesof the salt with acidic amino acid include a salt with aspartic acid,glutamic acid and the like.

Of these, pharmaceutically acceptable salts are preferable. For example,when a compound contains an acidic functional group, inorganic saltssuch as alkali metal salt (e.g., sodium salt, potassium salt etc.),alkaline earth metal salt (e.g., calcium salt, magnesium salt, bariumsalt etc.) and the like, ammonium salt and the like; and when a compoundcontains a basic functional group, for example, salts with inorganicacid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuricacid, phosphoric acid and the like, or salts with organic acid such asacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid,maleic acid, citric acid, succinic acid, methanesulfonic acid,p-toluenesulfonic acid and the like can be mentioned.

compound (I) can be produced, for example, according to the methodsdescribed in JP application No. 2005-044740, Eur. J. Org. Chem., p. 2283(2001), J. Med. Chem., vol. 43, p. 1886 (2000), J. Pharm. Pharmacol.,vol. 46, p. 740 (1994), WO92/04025, J. Heterocycl. Chem., vol. 25, p.635 (1988), J. Med. Chem., vol. 14, p. 328 (1971), J. Med. Chem., vol.35, p. 4195 (1992) or Tetrahedron Lett., vol. 26, p. 4047 (1985), or amethod analogous thereto.

The production methods of compound (I) in the present invention areexplained by referring to the production methods of compound (VIII),(XI), (XIV), (XVI) and (XVII).

The compounds (VIII), (XI), (XIV), (XVI) and (XVII) of the presentinvention can be produced, for example, by the method shown by thefollowing scheme or a method analogous thereto and the like.

The compounds (III)-(XVII) in the formulas may form salts, and as suchsalts, for example, those similar to the salts of compound (I) can bementioned.

While the compounds obtained in respective steps can be used for thenext reaction in the form of a reaction mixture or a crude product, theycan also be easily isolated and purified from the reaction mixture by aknown separation and purification means, such as recrystallization,distillation, chromatography and the like.

Compound (III) wherein R², R³ and R⁴ are as defined above, and R⁴⁷ is aC₁₋₄ alkyl group such as methyl, ethyl, propyl, isopropyl, butyl and thelike can be produced according to a method known per se, such as themethod described in Chem. Pharm. Bull., vol. 49, p. 1406 (2001),Tetrahedron Letters, vol. 35, p. 5989 (1994) and the like or a methodanalogous thereto.

By acylation, alkylation and the like of compound (III), compound (IV)(wherein each symbol is as defined above) can be produced, which is acompound (III) wherein the 1-position of pyrrole ring is substituted by—X—R¹.

The acylation can be conducted using an acylating agent such as acidhalide (e.g., carbonyl halide, sulfonyl halide and the like (e.g.,benzoyl chloride)), acid anhydride (e.g., benzoic anhydride),chlorocarbonate (e.g., chlorobenzyl formate), carbamoyl chloride (e.g.,phenylcarbamoyl chloride), sulfamoyl chloride (e.g., benzylsulfamoylchloride) and the like. The alkylation can be conducted using analkylating agent having a leaving group such as a halogen atom (e.g., achlorine atom, a bromine atom, an iodine atom), an alkylsulfonyloxygroup (e.g., a mesyloxy group), an arylsulfonyloxy group (e.g., atosyloxy group) and the like (e.g., benzyl bromide, benzylmethanesulfonate or benzyl 4-methylbenzenesulfonate etc.).

This reaction is advantageously carried out using a solvent inert to thereaction. While the solvent is not particularly limited as long as thereaction proceeds, hydrocarbons such as benzene, toluene and the like,tetrahydrofuran, amides such as N,N-dimethylformamide,N,N-dimethylacetamide and the like, and the like or a mixed solventthereof and the like are preferable.

Use of a base is effective for the reaction. As the base, for example,inorganic bases such as sodium hydroxide, potassium hydroxide and thelike, basic salts such as sodium carbonate, potassium carbonate, cesiumcarbonate, sodium hydrogencarbonate and the like, aromatic amines suchas pyridine, lutidine and the like, tertiary amines such astriethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine and the like, and the like canbe mentioned. The amount of the base to be used is about 0.1-about 10mol, preferably about 1-about 5 mol, per 1 mol of compound (III).

While the reaction time varies depending on the reagents and solvents tobe used, it is generally about 30 min-about 24 hr, preferably about 30min-about 8 hr.

The reaction temperature is generally about 0° C.-about 250° C.,preferably about 25° C.-about 100° C.

The compound (IV) can be easily converted to compound (V) (wherein eachsymbol is as defined above) by hydrolysis.

The hydrolysis can be conducted according to the method described inShin Jikken Kagaku Koza, vol. 14-II, page 930-941 (Maruzen Press).

By esterification or amidation reaction of the present compound (V) anda compound represented by the formula (VI)

wherein Y′ is a bond or a spacer having 1 to 20 atoms in the main chain,and other symbols are as defined above, or a compound represented by theformula (VII)

wherein R⁴⁹ is a hydrogen atom or an alkyl group (preferably a C₁₋₆alkyl group) such as methyl group, ethyl group and the like, and othersymbols are as defined above, compound (VIII)wherein R⁴⁸ is —O— or —NR⁴⁹— (R⁴⁹ is as defined above), and othersymbols are as defined above can be produced.

As the “spacer having 1 to 20 carbon atoms in the main chain” for Y′, agroup similar to the above-mentioned Y can be mentioned, and —(CH₂)₂₋₆—and the like are preferable.

As compound (VI), for example, N,N-dimethylethanolamine,3-dimethylamino-1-propanol, 4-dimethylamino-1-butanol and the like, andas compound (VII), for example, N,N-dimethylethylenediamine,N,N,N′-trimethylethylenediamine, N,N-dimethyl-N′-ethylethylenediamineand the like can be mentioned.

This synthetic reaction can be conducted in a solvent inert to thereaction, for example, by a coupling reaction usingN,N′-dicyclohexylcarbodiimide and N-hydroxysuccinimide or1-hydroxybenzotriazole and the like in combination. While the solvent isnot particularly limited as long as the reaction proceeds, solvents suchas tetrahydrofuran, amides (e.g., N,N-dimethylformamide,N,N-dimethylacetamide and the like), halogenated hydrocarbons such asdichloromethane and the like, and the like or a mixed solvent thereofand the like are preferable.

While the reaction time varies depending on the reagents and solvents tobe used, it is generally about 30 min-about 24 hr, preferably about 30min-about 8 hr.

The reaction temperature is generally about −20° C.-about 50° C.,preferably about 0° C.-about 25° C.

By subjecting compound (IV) to a reduction reaction according to themethod described in Shin Jikken Kagaku Koza, vol. 14-I, pages 474-476(Maruzen Press), the compound can be easily converted to compound (IX)wherein each symbol is as defined above.

By reacting the present compound (IX) with a compound represented by theformula (X)

wherein R⁵⁰ is a leaving group such as a halogen atom (e.g., a chlorineatom, a bromine atom, an iodine atom), an alkylsulfonyloxy group (e.g.,mesyloxy group), an arylsulfonyloxy group (e.g., tosyloxy group) and thelike, and other symbols are as defined above, compound (XI) wherein eachsymbol is as defined above can be produced.

As compound (X), for example, 2-dimethylaminoethyl chloride,3-dimethylaminopropyl chloride and the like can be mentioned.

This reaction can be conducted under conditions as in the productionmethod of the aforementioned compound (IV).

Compound (IX) can be easily converted to a compound (XII) wherein eachsymbol is as defined above by a method known per se, for example,oxidation reaction described in Synthesis, page 639 (1994). Bysubjecting the present compound (XII) and a compound represented by theformula (XIII)

wherein each symbol is as defined above to a reductive aminationreaction according to the method described in Shin Jikken Kagaku Koza,vol. 14-III, pages 1380-1385 (Maruzen Press), the compound can beconverted to compound (XIV) (wherein the symbols in the formula are asdefined above).

Compound (XVI) wherein n is an integer of 2 to 10, and other symbols areas defined above can be produced by subjecting compound (XII) and acompound represented by the formula (XV)

wherein each symbol is as defined above and Ph is phenyl, to a Wittigreaction according to the method described in, for example, J. Am. Chem.Soc., vol. 107, page 217 (1985) or Shin Jikken Kagaku Koza, vol. 14-I,pages 224-243 (Maruzen Press).

Compound (XV) can be produced according to a method known per se, forexample, the method described in J. Am. Chem. Soc., vol. 107, page 217(1985) and the like, or a method analogous thereto.

Compound (XVI) can be converted to compound (XVII) (the symbols in theformula are as defined above) by subjecting the compound to a reductionreaction according to the method described in Shin Jikken Kagaku Koza,vol. 14-I, pages 1-5 (Maruzen Press).

The production methods of compound (II) of the present invention aredescribed in more detail in the following.

Compound (II) of the present invention can be obtained, for example, bythe method shown in the following scheme or a method analogous theretoand the like.

Compound (XVIII)-(XXIII) in the formulas may form a salt, and as suchsalts, for example, those similar to the salts of compound (I) can beused.

In addition, the compound obtained in each step can be used for the nextreaction in the form of a reaction mixture as it is or as a crudeproduct. However, it can also be isolated from the reaction mixtureaccording to a conventional method, and easily purified by a separationmeans such as recrystallization, distillation, chromatography and thelike.

Compound (XVIII) wherein R⁵¹ is a C₁₋₄ alkyl group such as methyl,ethyl, propyl, isopropyl or butyl and the like, and other symbols are asdefined above can be produced according to a method known per se, forexample, the method described in Chem. Pharm. Bull., vol. 49, page 1406(2001), Tetrahedron Letters, vol. 35, page 5989 (1994) and the like, ora method analogous thereto. Compound (XIX) wherein each symbol is asdefined above can be produced according to a method known per se, forexample, the method described in Chem. Ber., vol. 114, page 564 (1981)and the like, or a method analogous thereto.

Compound (XX) wherein each symbol is as defined above can be produced bysulfonylation of compound (XVIII) or compound (XIX) using C₁₋₅alkylsulfonyl chloride (e.g., mesyl chloride), arylsulfonyl chloride(e.g., tosyl chloride) and the like, or sulfamoylation of compound(XVIII) using C₁₋₅ alkylsulfamoyl chloride (e.g., methylsulfamoylchloride, ethylsulfamoyl chloride etc.) or arylsulfamoyl chloride (e.g.,phenylsulfamoyl chloride etc.) and the like.

This reaction is advantageously carried out in a solvent inert to thereaction. While the solvent is not particularly limited as long as thereaction proceeds, solvents such as hydrocarbons (e.g., benzene, tolueneand the like), tetrahydrofuran and amides (e.g., N,N-dimethylformamide,N,N-dimethylacetamide and the like) and the like or a mixed solventthereof and the like are preferable.

In a certain reaction, the use of a base may be effective. As the base,for example, inorganic bases such as sodium hydroxide, potassiumhydroxide and the like, basic salts such as sodium carbonate, potassiumcarbonate, cesium carbonate, sodium hydrogencarbonate and the like,metal bases such as potassium ethoxide, potassium tert-butoxide, sodiummethoxide, sodium ethoxide and the like, aromatic amines such aspyridine, lutidine and the like, tertiary amines such as triethylamine,tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine and the like and the like can bementioned. The amount of the base to be used is about 0.1-about 10 mol,preferably about 1-about 5 mol, per 1 mol of compound (XVIII) or (XIX).

In addition, for this reaction, addition of crown ether may beeffective. As the crown ether, for example, 15-crown-5-ether,18-crown-6-ether and the like can be mentioned. The amount of crownether to be used is about 1-about 10 mol, preferably about 1-about 5mol, per 1 mol of compound (II).

While the reaction time varies depending on the reagents and solvents tobe used, it is generally about 30 min-about 24 hr, preferably about 30min-about 8 hr.

The reaction temperature is generally about 0° C.-about 250° C.,preferably about 25° C.-about 100° C.

A compound (XX) wherein spacer X⁵ is an oxygen atom can be producedaccording to a method known per se, for example, the method described inJ. Org. Chem., vol. 53, page 2268 (1988) and the like, or a methodanalogous thereto.

Compound (XXI) (each symbol in the formula is as defined above) can besynthesized by reducing compound (XX) with a reducing agent such aslithium aluminum hydride, diisobutyl aluminum hydride, sodiumtetrahydroborate, calcium bis(tetrahydroborate) and the like. As thereducing agent, diisobutyl aluminum hydride is particularly preferable.

This reaction is advantageously carried out using a solvent inert to thereaction. While the solvent is not particularly limited as long as thereaction proceeds, solvents such as hydrocarbons (e.g., benzene, tolueneand the like) and ethers (e.g., tetrahydrofuran, diethyl ether and thelike), and the like, a mixed solvent thereof and the like arepreferable.

While the reaction time varies depending on the reagents and solvent tobe used, it is generally about 30 min-about 24 hr, preferably about 30min-about 8 hr.

The reaction temperature is generally about −78° C. to about 100° C.,preferably about −78° C. to about 25° C.

compound (XXII) (each symbol in the formula is as defined above) can besynthesized by reacting compound (XXI) with an oxidant such as chromicacid-pyridine complex, pyridinium chlorochromate, manganese dioxide,sulfur trioxide-pyridine complex or tetra-n-propylammonium perruthenateand the like. As the oxidant, manganese dioxide, sulfurtrioxide-pyridine complex or tetra-n-propylammonium perruthenate isparticularly preferable. The oxidation reaction can be carried out, forexample, according to the method described in Synthesis, p. 639 (1994).

Compound (II) wherein Y⁵ is a methylene chain can be produced bysubjecting compound (XXII) and a compound represented by the formula(XIII′):

wherein each symbol in the formula is as defined above, to a reductiveamination reaction according to the methods described in Shin JikkenKagaku Koza, Vols. 14-III, pp. 1380-1385 (Maruzen Press).

By reacting compound (XXII) with a compound represented by the formula(XV′)

wherein each symbol is as defined above by an operation similar to theproduction method of the aforementioned compound (XVI), the compound canbe converted to compound (XXIII) (wherein each symbol is as definedabove), and compound (XXIII) can be converted to a compound (II) whereinY⁵ is an alkylene chain by conducting a reduction reaction according toan operation similar to the production method of the aforementionedcompound (XVII).

The production method of compound (I) wherein X is —SO₂— is furtherexplained in detail by referring to the production methods of compounds(XXXIII) and (XXXX).

Compound (XXIV) (wherein each symbol is as defined above) can beproduced according to a method known per se, for example, the methoddescribed in Tetrahedron Letters, vol. 13, page 5337 (1972),Heterocycles, vol. 7, page 77 (1977), Chem. Pharm. Bull., vol. 27, page2857 (1979), J. Org. Chem., vol. 62, page 2649 (1997) and the like, or amethod analogous thereto.

By reacting N-bromosuccinimide (NBS) with compound (XXIV), compound(XXV) wherein each symbol is as defined above can be produced.

This reaction is advantageously carried out using a solvent inert to thereaction. While the solvent is not particularly limited as long as thereaction proceeds, solvents such as ethers (e.g., tetrahydrofuran,diethyl ether and the like), amides (e.g., N,N-dimethylformamide,N,N-dimethylacetamide and the like) and the like or a mixed solventthereof and the like are preferable.

While the reaction time varies depending on the reagents and solvents tobe used, it is generally about 30 min-about 24 hr, preferably about 5-12hr.

The reaction temperature is generally about −78° C.-about 25° C.,preferably about −40° C.-about 0° C.

N-bromosuccinimide (NBS) is preferably used in about 1 equivalent amountrelative to compound (XXIV), and the reaction is preferably carried outin an inert gas atmosphere of nitrogen, argon and the like.

In this reaction, addition of a base may sometimes be effective. Whilethe base to be used is not limited as long as the reaction proceeds,organic bases such as pyridine, picoline, lutidine and the like, and thelike can be mentioned. The amount of the organic base to be used isabout 0.001-about 10 equivalents, preferably about 0.001-about 0.1equivalent, per 1 mol of compound (XXIV).

By reacting compound (XXV) with a compound represented by the formula(XXVI)

wherein each symbol is as defined above, compound (XXVII) wherein eachsymbol is as defined above can be produced.

This reaction is advantageously carried out using a solvent inert to thereaction. While the solvent is not particularly limited as long as thereaction proceeds, solvents such as hydrocarbons (e.g., benzene, tolueneand the like), ethers (e.g., tetrahydrofuran and the like), amides(e.g., N,N-dimethylformamide, N,N-dimethylacetamide and the like) andthe like or a mixed solvent thereof and the like are preferable.

For this reaction, the use of a base is effective. As the base, forexample, inorganic bases such as sodium hydride, sodium hydroxide,potassium hydroxide and the like, basic salts such as sodium carbonate,potassium carbonate, cesium carbonate, sodium hydrogencarbonate and thelike, metal bases such as potassium ethoxide, potassium tert-butoxide,sodium methoxide, sodium ethoxide and the like, aromatic amines such aspyridine, lutidine and the like, tertiary amines such as triethylamine,tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine and the like, and the like canbe mentioned. The amount of the base to be used is about 1-about 10 mol,preferably about 1-about 5 mol, per 1 mol of compound (XXV).

This reaction can also be carried out in the co-presence of crownethers. As the crown ether, for example, 15-crown-5-ether,18-crown-6-ether and the like can be mentioned. The amount of the crownether to be used is, about 1-about 10 mol, preferably about 1-about 5mol, per 1 mol of compound (XXV).

While the reaction time varies depending on the reagents and solvents tobe used, it is generally about 30 min-about 24 hr, preferably about 30min-about 8 hr.

The reaction temperature is generally about 0° C.-about 100° C.,preferably about 10° C.-about 50° C.

By reacting compound (XXVII) with a compound represented by the formula(XXVIII)

wherein each symbol is as defined above, according to the methoddescribed in Synthetic Communications, vol. 11, page 513 (1981), or amethod analogous thereto, compound (XXIX) wherein each symbol is asdefined above can be produced.

Compound (XXIX) can be converted to compound (XXX) wherein each symbolis as defined above, by a method similar to the production method ofcompound (XXI).

Compound (XXX) can be converted to compound (XXXI) wherein each symbolis as defined above by a method similar to the production method ofcompound (XXII).

Compound (XXXI) can be converted to compound (XXXIII) wherein eachsymbol is as defined above and Y is an alkylene chain by a methodsimilar to the production method of compound (XIV) from compound (XII).

Compound (XXVII) can be converted to compound (XXXIV) by a methodsimilar to the production method of compound (XXI).

Compound (XXXIV) (wherein each symbol is as defined above) can beconverted to compound (XXXV) (wherein each symbol is as defined above)by a method similar to the production method of compound (XXII).

By reacting compound (XXXV) with a compound represented by the formula(XXXVI)

R⁵⁶—NH₂  (XXXVI)

wherein R⁵⁶ is an optionally substituted hydrocarbon group, compound(XXXVII) (wherein each symbol is as defined above) can be produced by amethod similar to the production method of compound (II) from compound(XXII).

As the “optionally substituted hydrocarbon group” for R⁵⁶, a groupsimilar to the “optionally substituted hydrocarbon group” for theaforementioned R⁴⁰ can be mentioned.

Compound (XXXVII) can be converted to compound (XXXIX) (wherein eachsymbol is as defined above) by converting the compound to compound(XXXVIII) wherein R⁵⁷ is an amino-protecting group (e.g.,tert-butylcarbamate group [BOC group], benzylcarbamate group (Cbz group)and the like), and other symbols are as defined above by protecting anamino group according to a method known per se, for example, the methoddescribed in Protective Groups in Organic Synthesis, 3^(rd) Ed.(Theodora W. Greene, Peter G. M. Wuts), pages 494-653,Wiley-Interscience, 1999, and the like, and then by a method similar tothe production method of compound (XXIX).

Compound (XXXIX) can be converted to compound (XXXX) (wherein eachsymbol is as defined above) by eliminating the amino-protecting group bya method known per se, for example, the method described in ProtectiveGroups in Organic Synthesis, 3^(rd) Ed. (Theodora W. Greene, Peter G. M.Wuts), pages 494-653, Wiley-Interscience, 1999, and the like.

Compound (III) can be converted to compound (XXXXI) (wherein each symbolis as defined above) by a method similar to the production method ofcompound (XXI).

Compound (XXXXI) can be converted to compound (XXXXII) (wherein eachsymbol is as defined above) by a method similar to the production methodof compound (XXII).

Compound (XXXXII) can be converted to compound (XXXXIII) (wherein eachsymbol is as defined above) by a method similar to the production methodof compound (XXXVII).

Compound (XXXXIII) can be converted to compound (XXXIX) (wherein eachsymbol is as defined above) by converting the compound to compound(XXXXIV) (wherein each symbol is as defined above) by protecting anamino group according to a method known per se, for example, the methoddescribed in Protective Groups in Organic Synthesis, 3^(rd) Ed.(Theodora W. Greene, Peter G. M. Wuts), pages 494-653,Wiley-Interscience, 1999, and the like, and then by a method similar tothe production method of compound (XXVII).

Compound (XXXIX) can be converted to compound (XXXX) (wherein eachsymbol is as defined above) by eliminating the amino-protecting group bya method known per se, for example, the method described in ProtectiveGroups in Organic Synthesis, 3^(rd) Ed. (Theodora W. Greene, Peter G. M.Wuts), pages 494-653, Wiley-Interscience, 1999, and the like.

In addition, compounds (XXXV), (XXXI) and (XXXIII) can also be producedby the following methods.

Compound (XXIV) wherein each symbol is as defined above can be convertedto compound (XXXXV) wherein each symbol is as defined above by a methodsimilar to the production method of compound (XXVII).

Compound (XXXXV) wherein each symbol is as defined above can beconverted to compound (XXXXVI) wherein each symbol is as defined aboveby a method similar to the production method of compound (XXI).

Compound (XXXXVI) wherein each symbol is as defined above can beconverted to compound (XXXXVII) wherein each symbol is as defined aboveby a method similar to the production method of compound (XXII).

Compound (XXXXVII) wherein each symbol is as defined above can beconverted to compound (XXXV) wherein each symbol is as defined above bya method similar to the production method of compound (XXV).

Compound (XXXV) wherein each symbol is as defined above can be convertedto compound (XXXI) wherein each symbol is as defined above by a methodsimilar to the production method of compound (XXIX).

Compound (XXXXII) wherein each symbol is as defined above can beconverted to compound (XXXI) wherein each symbol is as defined above bya method similar to the production method of compound (XXVII).

Compound (XXXI) wherein each symbol is as defined above can be convertedto compound (XXXIII) wherein each symbol is as defined above by theaforementioned method.

In each of the aforementioned reactions, when the starting compound hasan amino group, a carboxyl group or a hydroxyl group as a substituent, aprotecting group generally used in peptide chemistry and the like may beintroduced into these groups. In this case, by eliminating theprotecting group as necessary after the reaction, the objective compoundcan be obtained. Introduction and elimination of these protecting groupscan be performed by a method known per se, for example, the methoddescribed in Protective Groups in Organic Synthesis, 3rd Ed., TheodoraW. Greene, Peter G. M. Wuts, Wiley-Interscience (1999) and the like.

Compound (I) can be isolated and purified by a known means such as phasetransfer, concentration, solvent extraction, fractionation, liquidconversion, crystallization, recrystallization, chromatography and thelike.

When compound (I) is obtained as a free compound, it can be converted toa desired salt by a method known per se or a method analogous thereto;conversely, when compound (I) is obtained as a salt, it can be convertedinto a free form or another desired salt by a method known per se or amethod analogous thereto.

Compound (I) (or compound (II)) may be used as a prodrug. The prodrug ofcompound (I) means a compound which is converted to compound (I) underthe physiological condition in the body by a reaction with an enzyme,gastric acid, or the like, that is, a compound which is converted tocompound (I) by enzymatic oxidation, reduction, hydrolysis, and thelike; a compound which is converted to compound (I) by hydrolysis withgastric acid, and the like.

The prodrug of compound (I) includes a compound wherein the amino groupof compound (I) is modified with acyl, alkyl or phosphoryl (e.g., acompound wherein the amino group of compound (I) is modified witheicosanoyl, alanyl, pentylaminocarbonyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl, tetrahydrofuranyl,pyrrolidylmethyl, pivaloyloxymethyl or t-butyl, etc.); a compoundwherein the hydroxyl group of compound (I) is modified with acyl, alkyl,phosphoric acid or boric acid (e.g., a compound wherein the hydroxylgroup of compound (I) is modified with acetyl, palmitoyl, propanoyl,pivaloyl, succinyl, fumaryl, alanyl or dimethylaminomethylcarbonyl,etc.); a compound wherein a carboxy group of compound (I) is modified toester or amide (e.g., a compound wherein a carboxy group of compound (I)is modified to ethyl ester, phenyl ester, carboxymethyl ester,dimethylaminomethyl ester, pivaloyloxymethyl ester,ethoxycarbonyloxyethyl ester, phthalidyl ester,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester,cyclohexyloxycarbonylethyl ester or methylamide, etc.); and the like.These compounds can be produced from compound (I) by a method known perse.

In addition, the prodrug of compound (I) may be a compound, which isconverted to compound (I) under the physiological conditions, asdescribed in Pharmaceutical Research and Development, Vol. 7 (MoleculeDesign), pp. 163-198 (1990), published by Hirokawa Publishing Co.

When compound (I) contains isomers such as an optical isomer, astereoisomer, a regioisomer, a rotamer and the like, either isomer and amixture of these are also encompassed in compound (I). For example, whencompound (I) has an optical isomer, an optical isomer resolved from aracemate is also encompassed in compound (I). These isomers can beobtained as single products according to synthesis and separationmethods known per se (concentration, solvent extraction, columnchromatography, recrystallization, etc.).

The compound (I) may be a crystal, and both a single crystal and crystalmixtures are encompassed in compound (I). Crystals can be produced bycrystallization according to crystallization methods known per se.

The compound (I) may be a solvate (e.g., hydrate etc.) or a non-solvate,both of which are encompassed in the compound (I).

A compound labeled with an isotope (e.g., ³H, ¹⁴C, ³⁵S, ¹²⁵I and thelike) is also encompassed in the compound (I).

Compound (I) (or compound (II)) and a prodrug thereof of the presentinvention (hereinafter sometimes to be abbreviated as the compound ofthe present invention) have a proton pump inhibitory effect andeffectively suppress gastric acid secretion. In addition, since theyshow low toxicity (e.g., acute toxicity, chronic toxicity, genetictoxicity, reproductive toxicity, cardiotoxicity, drug interaction,carcinogenicity and the like) and high water-solubility, and aresuperior in the stability, in vivo kinetics (absorbability,distribution, metabolism, excretion and the like), and efficacyexpression, they are useful as pharmaceutical agents.

The compound of the present invention is useful for the prophylaxis ortreatment of peptic ulcer (e.g., gastric ulcer, gastric ulcer due topostoperative stress, duodenal ulcer, anastomotic ulcer, ulcer caused bynon-steroidal anti-inflammatory agents etc.); gastritis; erosiveesophagitis; gastroesophageal reflux disease (SymptomaticGastroesophageal Reflux Disease (symptomatic GERD)) free of esophagitisand the like; NUD (Non Ulcer Dyspepsia); gastric cancer (includinggastric cancer associated with promoted production of interleukin-1β dueto gene polymorphism of interleukin-1); stomach MALT lymphoma;Zollinger-Ellison syndrome; gastric hyperacidity (e.g., gastrichyperacidity and ulcer due to postoperative stress); uppergastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer,hemorrhagic gastritis or invasive stress (e.g. stress caused by majorsurgery requiring postoperative intensive management, andcerebrovascular disorder, head trauma, multiple organ failure andextensive burn, each requiring intensive treatment) and the like; andthe like, pre-anesthetic administration, eradication of Helicobacterpylori and the like, in mammals (e.g., human, simian, sheep, cattle,horse, dog, cat, rabbit, rat, mouse etc.).

As used herein, the above-mentioned reflux esophagitis andgastroesophageal reflux disease (Symptomatic Gastroesophageal RefluxDisease (symptomatic GERD)) free of esophagitis are sometimescollectively referred to simply as GERD.

The content of a compound of the present invention in the pharmaceuticalcomposition of the present invention is about 0.01 to 100% by weightrelative to the entire composition. Though subject to change dependingon the administration target, administration route, target disease andthe like, its dose is about 0.5 to about 1,500 mg/day, preferably about5 to about 150 mg/day, based on the active ingredient, when, forexample, the compound is orally administered as an anti-ulcer agent toan adult human (60 kg). The compound of the present invention may beadministered once daily or in 2 or 3 divided portions per day.

The compound of the present invention shows low toxicity and can besafely administered orally or parenterally (e.g., topical, rectal,intravenous administrations and the like) as it is or as a preparationcontaining a pharmaceutical composition containing a pharmacologicallyacceptable carrier admixed according to a method known per se, such astablets (including sugar-coated tablets and film-coated tablets),powder, granule, capsule (including soft capsule), orally disintegratingtablet, liquid, injection, suppository, sustained-release preparation,plaster and the like. Particularly, the compound of the presentinvention is preferably administered as an oral preparation in the formof tablet, granule, capsule and the like.

The pharmacologically acceptable carrier that may be used to produce thepharmaceutical composition of the present invention includes variousorganic or inorganic carrier substances in common use as pharmaceuticalmaterials, including excipients, lubricants, binders, disintegrants,water-soluble polymers and basic inorganic salts for solid preparations;and solvents, dissolution aids, suspending agents, isotonizing agents,buffers and soothing agents for liquid preparations and the like. Otherconventional additives such as preservatives, anti-oxidants, coloringagents, sweetening agents, souring agents, bubbling agents andflavorings may also be used as necessary.

Such “excipients” include, for example, lactose, sucrose, D-mannitol,starch, cornstarch, crystalline cellulose, light anhydrous silicic acid,titanium oxide and the like.

Such “lubricants” include, for example, magnesium stearate, sucrosefatty acid esters, polyethylene glycol, talc, stearic acid and the like.

Such “binders” include, for example, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, crystalline cellulose, starch,polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan,low-substituted hydroxypropyl cellulose and the like.

Such “disintegrants” include (1) crosspovidone, (2) what is calledsuper-disintegrants such as crosscarmellose sodium (FMC-Asahi Chemical)and carmellose calcium (Gotoku Yakuhin) etc, (3) carboxymethyl starchsodium (e.g., product of Matsutani Chemical), (4) low-substitutedhydroxypropyl cellulose (e.g., product of Shin-Etsu Chemical), (5) cornstarch, and so forth. Said “crosspovidone” may be any crosslinkedpolymer having the chemical name 1-ethenyl-2-pyrrolidinone homopolymer,including polyvinylpyrrolidone (PVPP) and 1-vinyl-2-pyrrolidinonehomopolymer, and is exemplified by Colidon CL (produced by BASF),Polyplasdon XL (produced by ISP), Polyplasdon XL-10 (produced by ISP),Polyplasdon INF-10 (produced by ISP) and the like.

Such “water-soluble polymers” include, for example, ethanol-solublewater-soluble polymers [e.g., cellulose derivatives such ashydroxypropyl cellulose (hereinafter also referred to as HPC) etc,polyvinylpyrrolidone and the like], ethanol-insoluble water-solublepolymers [e.g., cellulose derivatives such as hydroxypropylmethylcellulose (hereinafter also referred to as HPMC) etc., methyl cellulose,carboxymethyl cellulose sodium and the like, sodium polyacrylate,polyvinyl alcohol, sodium alginate, guar gum and the like] and the like.

Such “basic inorganic salts” include, for example, basic inorganic saltsof sodium, potassium, magnesium and/or calcium. Preferred are basicinorganic salts of magnesium and/or calcium. More preferred are basicinorganic salts of magnesium. Such basic inorganic salts of sodiuminclude, for example, sodium carbonate, sodium hydrogencarbonate,disodium hydrogenphosphate and the like. Such basic inorganic salts ofpotassium include, for example, potassium carbonate, potassiumhydrogencarbonate and the like. Such basic inorganic salts of magnesiuminclude, for example, heavy magnesium carbonate, magnesium carbonate,magnesium oxide, magnesium hydroxide, magnesium aluminometasilicate,magnesium silicate, magnesium aluminate, synthetic hydrotalcite[Mg₆Al₂(OH)₁₆.CO₃.4H₂O], and aluminum magnesium hydroxide. Preferred areheavy magnesium carbonate, magnesium carbonate, magnesium oxide,magnesium hydroxide and the like. Such basic inorganic salts of calciuminclude, for example, precipitated calcium carbonate, calcium hydroxide,etc.

Such “solvents” include, for example, water for injection, alcohol,propylene glycol, macrogol, sesame oil, corn oil, olive oil and thelike.

Such “dissolution aids” include, for example, polyethylene glycol,propylene glycol, D-mannitol, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodiumcitrate and the like.

Such “suspending agents” include, for example, surfactants such asstearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionicacid, lecithin, benzalkonium chloride, benzethonium chloride, glycerylmonostearate etc; hydrophilic polymers such as polyvinyl alcohol,polyvinylpyrrolidone, carboxymethyl cellulose sodium, methyl cellulose,hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl celluloseetc., and the like.

Such “isotonizing agents” include, for example, glucose, D-sorbitol,sodium chloride, glycerol, D-mannitol and the like.

Such “buffers” include, for example, buffer solutions of phosphates,acetates, carbonates, citrates etc, and the like.

Such “soothing agents” include, for example, benzyl alcohol and thelike.

Such “preservatives” include, for example, p-oxybenzoic acid esters,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid,sorbic acid and the like.

Such “antioxidants” include, for example, sulfites, ascorbic acid,α-tocopherol and the like.

Such “coloring agents” include, for example, food colors such as FoodColor Yellow No. 5, Food Color Red No. 2, Food Color Blue No. 2 etc.;food lake colors, red ferric oxide and the like.

Such “sweetening agents” include, for example, saccharin sodium,dipotassium glycyrrhizinate, aspartame, stevia, thaumatin and the like.

Such “souring agents” include, for example, citric acid (citricanhydride), tartaric acid, malic acid and the like.

Such “bubbling agents” include, for example, sodium bicarbonate and thelike.

Such “flavorings” may be synthetic substances or naturally occurringsubstances, and include, for example, lemon, lime, orange, menthol,strawberry and the like.

The compound of the present invention may be prepared as a preparationfor oral administration in accordance with a commonly-known method, by,for example, compression-shaping with a carrier such as an excipient, adisintegrant, a binder, a lubricant, or the like, and subsequentlycoating the preparation as necessary by a commonly known method for thepurpose of taste masking, enteric dissolution or sustained release. Foran enteric preparation, an intermediate layer may be provided by acommonly known method between the enteric layer and the drug-containinglayer for the purpose of separation of the two layers.

For preparing the compound of the present invention as an orallydisintegrating tablet, available methods include, for example, a methodin which a core containing crystalline cellulose and lactose is coatedwith the compound of the present invention and, where necessary, a basicinorganic salt, and then further coated with a coating layer containinga water-soluble polymer to give a composition, which is coated with anenteric coating layer containing polyethylene glycol, further coatedwith an enteric coating layer containing triethyl citrate, still furthercoated with an enteric coating layer containing polyethylene glycol, andfinally coated with mannitol to give fine granules, which are mixed withadditives and shaped.

The above-mentioned “enteric coating layer” includes, for example, alayer consisting of a mixture of one or more kinds from aqueous entericpolymer substrates such as cellulose acetate phthalate (CAP),hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetatesuccinate, methacrylic acid copolymers (e.g., Eudragit L30D-55 (tradename; produced by Rohm), Colicoat MAE30DP (trade name; produced byBASF), Polyquid PA30 (trade name; produced by San-yo Chemical) etc.),carboxymethylethyl cellulose, shellac and the like; sustained-releasesubstrates such as methacrylic acid copolymers (e.g., Eudragit NE30D(trade name), Eudragit RL30D (trade name), Eudragit RS30D (trade name),etc.) and the like; water-soluble polymers; plasticizers such astriethyl citrate, polyethylene glycol, acetylated monoglycerides,triacetin, castor oil and the like; and the like, and the like.

The above-mentioned “additive” includes, for example, water-solublesugar alcohols (e.g., sorbitol, mannitol, maltitol, reduced starchsaccharides, xylitol, reduced palatinose, erythritol, etc.), crystallinecellulose (e.g., Ceolas KG 801, Avicel PH 101, Avicel PH 102, Avicel PH301, Avicel PH 302, Avicel RC-591 (crystalline cellulose carmellosesodium) etc.), low-substituted hydroxypropyl cellulose (e.g., LH-22,LH-32, LH-23, LH-33 (Shin-Etsu Chemical), mixtures thereof etc.) and thelike. Furthermore, binders, souring agents, bubbling agents, sweeteningagents, flavorings, lubricants, coloring agents, stabilizers,excipients, disintegrants etc. are also used.

The compound of the present invention may be used in combination with 1to 3 other active ingredients.

Such “other active ingredients” include, for example, anti-Helicobacterpylori active substances, imidazole compounds, bismuth salts, quinolonecompounds, and so forth.

Such “anti-Helicobacter pylori active substances” include, for example,antibiotic penicillins (e.g., amoxicillin, benzylpenicillin,piperacillin, mecillinam, etc.), antibiotic cefems (e.g., cefixime,cefaclor, etc.), antibiotic macrolides (e.g., erythromycin,clarithromycin, etc.), antibiotic tetracyclines (e.g., tetracycline,minocycline, streptomycin, etc.), antibiotic aminoglycosides (e.g.,gentamicin, amikacin, etc.), imipenem and so forth. Of these substances,preferred are antibiotic penicillins, antibiotic macrolides and thelike.

Such “imidazole compounds” include, for example, metronidazole,miconazole and the like.

Such “bismuth salts” include, for example, bismuth acetate, bismuthcitrate and the like.

Such “quinolone compounds” include, for example, ofloxacin, ciploxacinand the like.

For eradication of Helicobacter pylori, a compound (I) or a salt thereofof the present invention with antibiotic penicillin (e.g., amoxicillinand the like) and antibiotic erythromycin (e.g., clarithromycin and thelike) is preferably used. When the compound of the present invention isused for the purpose of eradication of Helicobacter pylori, while thecompound of the present invention has an antibacterial activity againstH. pylori, when co-used with other active ingredient, it can enhance theantibacterial action of other antibiotics based on the pH controllingaction in the stomach and the like, in addition to the antibacterialactivity of the compound per se of the present invention, and alsoprovides an assistant effect such as an eradication effect based on theaction of the antibiotics to be used in combination.

Such “other active ingredients” and the compound (I) or a salt thereofof the present invention may be mixed, prepared as a singlepharmaceutical composition [e.g., tablets, powders, granules, capsules(including soft capsules), liquids, injectable preparations,suppositories, sustained-release preparations, etc.], according to amethod known per se for combined use, or may also be prepared asseparate preparations and administered to the same subjectsimultaneously or in a staggered manner.

EXAMPLES

The present invention is explained in detail in the following byreferring to Reference Examples, Examples and Experimental Examples,which are not to be construed as limitative.

In the following Reference Examples and Examples, the “room temperature”generally means about 10° C. to about 35° C., but it is not particularlystrictly limited. The mixing ratio of liquids shows a volume ratio.Unless otherwise specified, “%” means weight %. The yield is in mol/mol%. Silica gel column chromatography was performed using silica gel 60(0.063-0.200 mm) manufactured by MERCK or Fuji Silysia Chemical Ltd.Chromatorex (trade name) NH (described as basic silica gel columnchromatography). For ¹H-NMR spectrum, tetramethylsilane was used as theinternal standard, and Varian Gemini-200 (200 MHz), Mercury-300 (300MHz) spectrometer, Bruker AVANCE AV300 (300 MHz) spectrometer andJNM-AL400 (400 MHz) nuclear magnetic resonance apparatuses (JEOL DATUM(JEOL DATUM LTD.)) were used for the measurement. The followingabbreviations are used for showing the measurement results.

s: singlet, d: doublet, dd: double doublet, ddd: double double doublet,t: triplet, dt: double triplet, t: triplet, q: quartet, m: multiplet,br: broad, brs: broad singlet, brd: broad doublet, brt: broad triplet,J: coupling constant, Hz: Hertz.

Reference Example 1 Ethyl 2-cyano-4-oxo-4-phenylbutanoate

Potassium carbonate (13.82 g) was added to ethyl cyanoacetate (37 mL),and the mixture was stirred at 40-45° C. for 45 min. A solution (100 mL)of phenacyl bromide (10.0 g) in acetone was added dropwise over 30 min.After completion of the dropwise addition, and the mixture was stirredat room temperature for 18 hr. The reaction mixture was filtered, andthe filtrate was concentrated under reduced pressure. Water was added tothe residue, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. Excess ethylcyanoacetate contained in the obtained oil was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=8:1→1:1) to give the titlecompound as a pale-yellow oil (yield 10.41 g, 90%).

¹H-NMR (CDCl₃) δ: 1.35 (3H, t, J=7.2 Hz), 3.55 (1H, dd, J=16.0 Hz, 5.6Hz), 3.80 (1H, dd, J=16.0 Hz, 7.0 Hz), 4.16 (1H, dd, J=7.0 Hz, 5.6 Hz),4.31 (2H, q, J=7.2 Hz), 7.40-7.70 (3H, m), 7.90-8.00 (2H, m).

Reference Example 2 Ethyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate

To a solution (60 mL) of ethyl 2-cyano-4-oxo-4-phenylbutanoate (5.0 g)in tetrahydrofuran was blown in hydrogen chloride (28 g) underice-cooling, and the mixture was stirred at room temperature for 3 hr.Then, nitrogen was blown in to remove hydrogen chloride. The reactionmixture was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=6:1) to give the title compound as a pale-yellow solid (yield4.24 g, 79%).

¹H-NMR (CDCl₃) δ: 1.37 (3H, t, J=6.8 Hz), 4.33 (2H, q, J=6.8 Hz), 6.87(1H, d, J=3.2 Hz), 7.20-7.60 (5H, m), 8.79 (1H, br).

Reference Example 3 Ethyl 5-phenyl-1H-pyrrole-3-carboxylate

To a solution (50 mL) of ethyl2-chloro-5-phenyl-1H-pyrrole-3-carboxylate (8.5 g) in ethanol was added10% palladium carbon (50% water containing product, 0.5 g), and themixture was stirred under a hydrogen atmosphere at room temperature for24 hr. The reaction mixture was filtered, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=9:1→1:1) to givethe title compound as a colorless solid (yield 4.50 g, 62%).

¹H-NMR (CDCl₃) δ: 1.36 (3H, t, J=7.2 Hz), 4.31 (2H, q, J=7.2 Hz), 6.91(1H, m), 7.20-7.70 (6H, m), 8.77 (1H, br).

Reference Example 4 Ethyl1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate

Sodium hydride (60% in oil, 408 mg) was washed with hexane and added toN,N-dimethylformamide (5 mL). The mixture was cooled to 0° C., and asolution (5 mL) of ethyl 5-phenyl-1H-pyrrole-3-carboxylate (2.0 g) inN,N-dimethylformamide was added. After stirring at 0° C. for 30 min, asolution (10 mL) of tosyl chloride (1.94 g) in N,N-dimethylformamide wasadded, and the reaction mixture was stirred at room temperature for 1hr. Water was added, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=6:1→1:1) to give the title compound as a colorless oil (yield2.90 g, 84%).

¹H-NMR (CDCl₃) δ: 1.36 (3H, t, J=7.2 Hz), 2.36 (3H, s), 4.31 (2H, q,J=7.2 Hz), 6.52 (1H, d, J=1.8 Hz), 7.05-7.40 (9H, m), 8.07 (1H, d, J=1.8Hz).

Reference Example 5{1-[(4-Methylphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methanol

A solution (30 mL) of ethyl1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate (2.85 g)in tetrahydrofuran was cooled to −78° C., and a 1.5 mol/l toluenesolution (12.8 mL) of diisobutylaluminum hydride was added dropwise over30 min, and the mixture was further stirred at −78° C. for 1 hr. 1 mol/lHydrochloric acid (20 mL) was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=6:1→1:1) to give the titlecompound as a brown oil (yield 2.29 g, 91%).

¹H-NMR (CDCl₃) δ: 2.35 (3H, s), 4.55 (2H, d, J=4.8 Hz), 6.19 (1H, d,J=2.2 Hz), 7.09 (2H, d, J=8.4 Hz), 7.15-7.40 (8H, m).

Reference Example 61-[(4-Methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde

To a solution (10 mL) of{1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methanol (1.50 g)in acetonitrile were added tetra-n-propylammonium perruthenate (150 mg),N-methylmorpholine N-oxide (932 mg) and molecular sieves 4A powder (1.5g), and the mixture was stirred at room temperature for 1 hr. Thereaction mixture was concentrated under reduced pressure, and theresidue was suspended in ethyl acetate and filtered through celite. Thefiltrate was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=6:1→1:1) to give the title compound as a brown oil (yield 1.23g, 82%).

¹H-NMR (CDCl₃) δ: 2.37 (3H, s), 6.55 (1H, d, J=2.2 Hz), 7.05-7.50 (9H,m), 8.10 (1H, d, J=2.2 Hz), 9.87 (1H, s).

Reference Example 7{1-[(4-Fluorophenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methanol

A solution (5 mL) of ethyl 5-phenyl-1H-pyrrole-3-carboxylate (500 mg) inN,N-dimethylformamide was cooled to 0° C., and sodium hydride (60% inoil, 139 mg) was added after washing with hexane. The mixture wasfurther stirred at 0° C. for 30 min, 4-fluorobenzenesulfonyl chloride(542 mg) was added, and the mixture was stirred at room temperature for30 min. The reaction mixture was concentrated under reduced pressure,and water was added to the residue, and the mixture was extracted withethyl acetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was dissolved in tetrahydrofuran (10 mL) and the mixture wascooled to −78° C. A 1.5 mol/l toluene solution (3.86 mL) ofdiisobutylaluminum hydride was added dropwise, and the mixture wasfurther stirred at −78° C. for 1 hr. 1 mol/l Hydrochloric acid (20 mL)was added to the reaction mixture, and the mixture was extracted withethyl acetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→1:1) to give the title compound as a brown oil(yield 410 mg, 53%).

¹H-NMR (CDCl₃) δ: 4.57 (2H, d, J=5.0 Hz), 6.21 (1H, d, J=1.8 Hz), 6.97(2H, t, J=9.2 Hz), 7.15-7.45 (8H, m).

Reference Example 81-[(4-Fluorophenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde

Using {1-[(4-fluorophenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methanol(405 mg), tetra-n-propylammonium perruthenate (42 mg),N-methylmorpholine N-oxide (247 mg) and molecular sieves 4A powder (1.0g), a procedure as in Reference Example 6 was performed to give thetitle compound as a brown oil (yield 321 mg, 80%).

¹H-NMR (CDCl₃) δ: 6.57 (1H, d, J=1.8 Hz), 6.98 (2H, t, J=8.8 Hz),7.10-7.45 (7H, m), 8.10 (1H, d, J=1.8 Hz), 9.89 (1H, s).

Reference Example 9 [1-(Methylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]methanol

A solution (5 mL) of ethyl 5-phenyl-1H-pyrrole-3-carboxylate (500 mg) inN,N-dimethylformamide was cooled to 0° C., sodium hydride (60% in oil,140 mg) was added after washing with hexane. The mixture was stirred atroom temperature for 30 min, cooled to 0° C., and mesyl chloride (0.269mL) was added. The reaction mixture was stirred at room temperature for2 hr, and 1 mol/l hydrochloric acid (5 mL) was added. The mixture wasneutralized with saturated aqueous sodium hydrogen carbonate, andconcentrated under reduced pressure. Water was added to the residue, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=6:1→1:1). Theobtained colorless solid was dissolved in tetrahydrofuran (10 mL) andcooled to −78° C. A 1.5 mol/l solution (3.5 mL) of diisobutylaluminumhydride in toluene was added dropwise, and the mixture was furtherstirred at −78° C. for 1 hr. 1 mol/l Hydrochloric acid (20 mL) was addedto the reaction mixture, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→1:1) to give the title compound as a colorlesssolid (yield 230 mg, 39%).

¹H-NMR (CDCl₃) δ: 2.85 (3H, s), 4.60 (2H, d, J=4.4 Hz), 6.36 (1H, d,J=2.2 Hz), 7.20-7.60 (6H, m).

Reference Example 101-(Methylsulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde

Using [1-(methylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]methanol (220 mg),tetra-n-propylammonium perruthenate (31 mg), N-methylmorpholine N-oxide(177 mg) and molecular sieves 4A powder (500 mg), a procedure as inReference Example 6 was performed to give the title compound as a brownoil (yield 165 mg, 76%).

¹H-NMR (CDCl₃) δ: 2.88 (3H, s), 6.30 (1H, d, J=1.6 Hz), 7.20-7.60 (6H,m), 9.98 (1H, s).

Reference Example 11 Ethyl1-[(4-methoxyphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate

Using ethyl 5-phenyl-1H-pyrrole-3-carboxylate (250 mg), sodium hydride(60% in oil, 60 mg) and 4-methoxybenzenesulfonyl chloride (264 mg), aprocedure as in Reference Example 4 was performed to give the titlecompound as a colorless oil (yield 433 mg, 97%).

¹H-NMR (CDCl₃) δ: 1.37 (3H, t, J=7.4 Hz), 3.82 (3H, s), 4.30 (2H, q,J=7.4 Hz), 6.51 (1H, d, J=1.8 Hz), 6.74 (2H, d, J=9.0 Hz), 7.15-7.40(7H, m), 8.07 (1H, d, J=1.8 Hz).

Reference Example 121-[(4-Methoxyphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde

Ethyl 1-[(4-methoxyphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate(430 mg) was dissolved in tetrahydrofuran (10 mL), and the mixture wascooled to −78° C. A 1.5 mol/l solution (3.36 mL) of diisobutylaluminumhydride in toluene was added dropwise, and the mixture was furtherstirred at −78° C. for 1 hr. 1 mol/l Hydrochloric acid (20 mL) was addedto the reaction mixture, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was dissolved in acetonitrile (10 mL), tetra-n-propylammoniumperruthenate (39 mg), N-methylmorpholine N-oxide (227 mg) and molecularsieves 4A powder (500 mg) were added, and the mixture was stirred atroom temperature for 30 min. The reaction mixture was concentrated underreduced pressure, and the residue was suspended in ethyl acetate andfiltered through celite. The filtrate was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=9:1→1:1) to give the titlecompound as a brown oil (yield 249 mg, 65%).

¹H-NMR (CDCl₃) δ: 3.82 (3H, s), 6.55 (1H, d, J=1.8 Hz), 6.74 (2H, d,J=8.8 Hz), 7.15-7.45 (7H, m), 8.10 (1H, d, J=1.8 Hz), 9.87 (1H, s).

Reference Example 13 Ethyl 2-acetyl-4-oxo-4-phenylbutanoate

A solution (20 mL) of ethyl 3-oxobutanoate (6.37 mL) inN,N-dimethylformamide was cooled to 0° C., sodium hydride (60% in oil,2.4 g) was added after washing with hexane. The reaction mixture wasstirred at room temperature for 30 min and cooled to 0° C., and asolution (10 mL) of phenacyl bromide (10.0 g) in N,N-dimethylformamidewas added dropwise. The reaction mixture was stirred at room temperaturefor 30 min and concentrated under reduced pressure. Water was added tothe residue, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous sodiumsulfate, concentrated under reduced pressure to give the title compoundas a pale-yellow oil (yield 11.52 g, 93%).

¹H-NMR (CDCl₃) δ: 1.20-1.35 (3H, m), 2.45 (3H, s), 3.40-3.80 (2H, m),3.90-4.10 (1H, m), 4.15-4.30 (2H, m), 7.40-7.60 (3H, m), 7.90-8.00 (2H,m).

Reference Example 14 Ethyl 2-methyl-5-phenyl-1H-pyrrole-3-carboxylate

Ethyl 2-acetyl-4-oxo-4-phenylbutanoate (3.0 g) and ammonium acetate(1.39 g) were added to acetic acid (20 mL), and the mixture was stirredat 80° C. for 18 hr. The reaction mixture was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=9:1→1:1) to give the titlecompound as a brown solid (yield 1.25 g, 45%).

¹H-NMR (CDCl₃) δ: 1.37 (3, t, J=7.4 Hz), 2.59 (3H, s), 4.30 (2H, q,J=7.4 Hz), 6.83 (1H, d, J=3.0 Hz), 7.20-7.50 (5H, m), 8.40 (1H, br).

Reference Example 15 Ethyl1-[(4-fluorophenyl)sulfonyl]-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate

Using ethyl 2-methyl-5-phenyl-1H-pyrrole-3-carboxylate (500 mg), sodiumhydride (60% in oil, 175 mg) and 4-fluorobenzenesulfonyl chloride (848mg), a procedure as in Reference Example 4 was performed to give thetitle compound as a brown oil (yield 270 mg, 32%).

¹H-NMR (CDCl₃) δ: 1.35 (3H, t, J=8.8 Hz), 2.89 (3H, s), 4.26 (2H, q,J=8.8 Hz), 6.48 (1H, s), 7.05 (2H, t, J=8.0 Hz), 7.20-7.50 (7H, m).

Reference Example 161-[(4-Fluorophenyl)sulfonyl]-2-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde

Ethyl1-[(4-fluorophenyl)sulfonyl]-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate(380 mg) was dissolved in tetrahydrofuran (15 mL), and the mixture wascooled to −78° C. A 1.5 mol/l solution (1.96 mL) of diisobutylaluminumhydride in toluene was added dropwise, and the mixture was furtherstirred at −78° C. for 1 hr. 1 mol/l Hydrochloric acid (20 mL) was addedto the reaction mixture, and the mixture was stirred at room temperaturefor 15 min and extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=9:1→2:1). The obtainedbrown oil was dissolved in acetonitrile (5 mL), and the mixture wascooled to 0° C. Tetra-n-propylammonium perruthenate (34 mg),N-methylmorpholine N-oxide (172 mg) and molecular sieves 4A powder (500mg) were added, and the mixture was stirred at room temperature for 1hr. The reaction mixture was concentrated under reduced pressure, andthe residue was suspended in ethyl acetate, and filtered through celite.The filtrate was concentrated under reduced pressure, and the residuewas purified by silica gel column chromatography (eluent: hexane-ethylacetate=9:1→2:1) to give the title compound as a colorless oil (yield210 mg, 62%).

¹H-NMR (CDCl₃) δ: 2.90 (3H, s), 6.48 (1H, s), 7.05 (2H, t, J=9.4 Hz),7.15-7.45 (7H, m), 10.01 (1H, s).

Reference Example 175-(4-Fluorophenyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole-3-carbaldehyde

Using 4-fluorophenacyl bromide instead of phenacyl bromide, a procedureas in Reference Example 1 was performed to synthesize ethyl2-cyano-4-(4-fluorophenyl)-4-oxobutanoate, and procedures as inReference Examples 2, 3, 4, 5 and 6 were sequentially performed to givethe title compound as a colorless solid.

¹H-NMR (CDCl₃) δ: 2.39 (3H, s), 6.54 (1H, d, J=2.1 Hz), 7.00 (2H, t,J=8.4 Hz), 7.09-7.27 (6H, m), 8.10 (1H, d, J=1.8 Hz), 9.87 (1H, s).

Reference Example 185-(3-Methylphenyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole-3-carbaldehyde

Using 3-methylphenacyl bromide instead of phenacyl bromide, a procedureas in Reference Example 1 was performed to synthesize ethyl2-cyano-4-(3-methylphenyl)-4-oxobutanoate, and procedures as inReference Examples 2, 3, 4, 5 and 6 were sequentially performed to givethe title compound as a pale-brown oil.

¹H-NMR (CDCl₃): 2.29 (3H, s), 2.38 (3H, s), 6.52 (1H, d, J=2.1 Hz), 6.85(1H, s), 6.95-7.00 (1H, m), 7.10-7.22 (6H, m), 8.08 (1H, d, J=2.1 Hz),9.86 (1H, s).

Reference Example 195-(3-Fluorophenyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole-3-carbaldehyde

Using 3-fluorophenacyl bromide instead of phenacyl bromide, a procedureas in Reference Example 1 was performed to synthesize ethyl2-cyano-4-(3-fluorophenyl)-4-oxobutanoate, and procedures as inReference Examples 2, 3, 4, 5 and 6 were sequentially performed to givethe title compound as a pale-brown oil.

¹H-NMR (CDCl₃): δ2.39 (3H, s), 6.57 (1H, d, J=1.8 Hz), 6.79-6.85 (1H,m), 6.98-7.34 (7H, m), 8.11 (1H, d, J=1.8 Hz), 9.88 (1H, s).

Reference Example 201-[(2-Methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde

Using 2-methylbenzenesulfonyl chloride instead of tosyl chloride, aprocedure as in Reference Example 4 was performed to synthesize ethyl1-[(2-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate, andprocedures as in Reference Examples 5 and 6 were sequentially performedto give the title compound as a colorless oil.

¹H-NMR (CDCl₃): δ2.25 (3H, s), 6.58 (1H, d, J=2.0 Hz), 6.88-6.92 (1H,m), 7.00-7.02 (2H, m), 7.13-7.18 (4H, m), 7.26-7.30 (1H, m), 7.34-7.38(1H, m), 8.22 (1H, d, J=1.7 Hz), 9.91 (1H, s).

Reference Example 215-Phenyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrole-3-carbaldehyde

Using 4-trifluoromethylbenzenesulfonyl chloride instead of tosylchloride, a procedure as in Reference Example 4 was performed tosynthesize ethyl5-phenyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrole-3-carboxylate,and procedures as in Reference Examples 5 and 6 were sequentiallyperformed to give the title compound as a colorless solid.

¹H-NMR (CDCl₃): δ6.60 (1H, d, J=1.7 Hz), 7.13-7.16 (2H, m), 7.29-7.33(2H, m), 7.41-7.45 (3H, m), 7.58 (2H, d, J=8.6 Hz), 8.12 (1H, d, J=2.0Hz), 9.90 (1H, s).

Reference Example 221-[(4-Fluoro-2-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde

Using 4-fluoro-2-methylbenzenesulfonyl chloride instead of tosylchloride, a procedure as in Reference Example 4 was performed tosynthesize ethyl1-[(4-fluoro-2-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate,and procedures as in Reference Examples 5 and 6 were sequentiallyperformed to give the title compound as a pale-yellow oil.

¹H-NMR (CDCl₃): δ2.24 (3H, s), 6.53-6.59 (2H, m), 6.88 (1H, dd, J=9.2Hz, 2.6 Hz), 7.03-7.05 (2H, m), 7.16-7.21 (3H, m), 7.27-7.33 (1H, m),8.20-8.22 (1H, m), 9.91-9.92 (1H, m).

Reference Example 23 Ethyl 2-cyano-4-(2-methylphenyl)-4-oxobutanoate

2′-Methylacetophenone (13.42 g) was dissolved in diethyl ether (100 mL),and bromine (16.0 g) was added dropwise while maintaining the reactiontemperature at not higher than 25° C. After dropwise addition, themixture was stirred at room temperature for 30 min. Water was added tothe reaction mixture and the mixture was extracted with diethyl ether.The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure to give crude1-bromo-1-(2-methylphenyl)ethanone (21.3 g) as an oil. To ethylcyanoacetate (79.20 g) was added potassium carbonate (27.64 g), and themixture was stirred at 43-45° C. for 45 min. A solution (150 mL) ofcrude 1-bromo-1-(2-methylphenyl)ethanone (21.3 g) in acetone was addeddropwise over 30 min. After completion of the dropwise addition, themixture was stirred at room temperature for 16 hr. The reaction mixturewas filtrated, and the filtrate was concentrated under reduced pressure.Water was added to the residue, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure. Anexcess ethyl cyanoacetate contained in the obtained oil was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (eluent: hexane-ethyl acetate=10:1→8:1) to givethe title compound as a pale-yellow oil (yield 46.44 g, about 100%).

¹H-NMR (CDCl₃) δ: 1.35 (3H, t, J=7.9 Hz), 2.53 (3H, s), 3.50 (1H, dd,J=5.2, 18.7 Hz), 3.71 (1H, dd, J=7.1, 17.9 Hz), 4.11-4.20 (1H, m), 4.31(2H, q, J=7.9 Hz), 7.25-7.34 (2H, m), 7.41-7.49 (1H, m), 7.72 (1H, d,J=7.7 Hz).

Reference Example 24 Ethyl 2-cyano-4-(4-methoxyphenyl)-4-oxobutanoate

4′-Methoxyacetophenone (15.0 g) was dissolved in chloroform (70 mL) anddiethyl ether (50 mL), and a solution of bromine (16.0 g) in chloroform(20 mL) was added dropwise while maintaining the reaction temperature atnot higher than 25° C. After dropwise addition, the mixture was stirredat room temperature for 2 hr. Water was added to the reaction mixtureand the mixture was extracted with chloroform. The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure to give crude1-bromo-1-(4-methoxyphenyl)ethanone (yield 22.05 g) as crystals. Toethyl cyanoacetate (79.20 g) was added potassium carbonate (27.65 g),and the mixture was stirred at 45° C. for 1 hr. A solution (100 mL) ofcrude 1-bromo-1-(4-methoxyphenyl)ethanone (22.0 g) in acetone was addeddropwise over 20 min. After completion of the dropwise addition, themixture was stirred at room temperature for 18 hr. The reaction mixturewas filtered, and the filtrate was concentrated under reduced pressure.Water was added to the residue, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure. Anexcess ethyl cyanoacetate contained in the obtained oil was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (eluent: hexane-ethyl acetate=9:1→3:1) to give thetitle compound as an oil (yield 30.25 g, about 100%).

¹H-NMR (CDCl₃) δ: 1.35 (3H, t, J=7.2 Hz), 3.45-3.56 (1H, m), 3.68-3.79(1H, m), 3.89 (3H, s), 4.08-4.20 (1H, m), 4.31 (2H, q, J=7.2 Hz), 6.96(2H, d, J=8.9 Hz), 7.95 (2H, d, J=8.9 Hz).

Reference Example 25 Ethyl2-cyano-4-oxo-4-[(2-trifluoromethylphenyl)butanoate

2′-(Trifluoromethyl)acetophenone (10.0 g) was dissolved in chloroform(30 mL) and diethyl ether (30 mL), a solution of bromine (8.50 g) inchloroform (20 mL) was added dropwise while maintaining the reactiontemperature at not higher than 25° C. After the dropwise addition, themixture was stirred at room temperature for 1 hr, water was added to thereaction mixture and the mixture was extracted with chloroform. Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate, concentrated under reduced pressure to give crude1-bromo-1-(2-trifluoromethylphenyl)ethanone. Potassium carbonate (13.82g) was added to ethyl cyanoacetate (44.44 g), and the mixture wasstirred at 45° C. for 1 hr. A solution (100 mL) of crude1-bromo-1-(2-trifluoromethylphenyl)ethanone in acetone was addeddropwise. After completion of the dropwise addition, the mixture wasstirred at the same temperature for 1 hr, and stirred overnight at roomtemperature. The reaction mixture was filtered, and the filtrate wasconcentrated under reduced pressure. Water was added to the residue, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. Excess ethyl cyanoacetate containedin the obtained oil was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→7:1) to give the title compound as an oil(yield 10.43 g, from 2′-(trifluoromethyl)acetophenone, 66%).

¹H-NMR (CDCl₃) δ: 1.36 (3H, t, J=7.2 Hz), 3.34-3.46 (1H, m), 3.59-3.70(1H, m), 4.08-4.22 (1H, m), 4.32 (2H, q, J=7.2 Hz), 7.57-7.80 (4H, m).

Reference Example 26 Ethyl 5-(4-methoxyphenyl)-1H-pyrrole-3-carboxylate

Using ethyl 2-cyano-4-(4-methoxyphenyl)-4-oxobutanoate, procedures as inReference Example 2 and 3 were performed to give the title compound ascolorless crystals.

¹H-NMR (CDCl₃) δ: 1.36 (3H, t, J=7.1 Hz), 3.83 (3H, s), 4.31 (2H, q,J=7.1 Hz), 6.79 (1H, d, J=1.2 Hz), 6.93 (2H, d, J=8.9 Hz), 7.38-7.46(3H, m), 8.60 (1H, brs).

Reference Example 27 Ethyl5-(2-trifluoromethylphenyl)-1H-pyrrole-3-carboxylate

Using ethyl 2-cyano-4-oxo-4-(2-trifluoromethylphenyl)butanoate,procedures as in Reference Example 2 and 3 were performed to give thetitle compound as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.36 (3H, t, J=7.2 Hz), 4.31 (2H, q, J=7.2 Hz), 6.81(1H, s), 7.42-7.61 (5H, m), 8.69 (1H, br).

Reference Example 28 Ethyl5-(4-fluorophenyl)-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate

Using 4-fluorophenacyl bromide instead of phenacyl bromide, a procedureas in Reference Example 1 was performed to synthesize ethyl2-cyano-4-(4-fluorophenyl)-4-oxobutanoate, and procedures as inReference Examples 2 and 3 were performed to synthesize ethyl5-(4-fluorophenyl)-1H-pyrrole-3-carboxylate. Sodium hydride (60% in oil,0.32 g) was added to a solution (20 mL) of ethyl5-(4-fluorophenyl)-1H-pyrrole-3-carboxylate (1.56 g) inN,N-dimethylformamide under ice-cooling. The mixture was stirred at thesame temperature for 15 min, added benzenesulfonyl chloride (1.41 g),and the mixture was stirred at room temperature for 18 hr. Water wasadded to the reaction mixture, and the mixture was extracted withdiethyl ether. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1→7:2) to give the title compound as crystals(yield 1.70 g, 68%).

¹H-NMR (CDCl₃) δ: 1.36 (3H, t, J=7.2 Hz), 4.31 (2H, q, J=7.2 Hz), 6.52(1H, d, J=1.9 Hz), 6.98 (2H, t, J=8.7 Hz), 7.12 (2H, dd, J=5.5 Hz, 8.7Hz), 7.33-7.35 (4H, m), 7.50-7.60 (1H, m), 8.09 (1H, d, J=1.9 Hz).

Reference Example 29 Ethyl5-(4-fluorophenyl)-1-[(4-fluorophenyl)sulfonyl]-1H-pyrrole-3-carboxylate

Using 4-fluorophenacyl bromide instead of phenacyl bromide, a procedureas in Reference Example 1 was performed to synthesize ethyl2-cyano-4-(4-fluorophenyl)-4-oxobutanoate, and procedures as inReference Examples 2 and 3 were performed to synthesize ethyl5-(4-fluorophenyl)-1H-pyrrole-3-carboxylate. Sodium hydride (60% in oil,0.58 g) was added to a solution (20 mL) of ethyl5-(4-fluorophenyl)-1H-pyrrole-3-carboxylate (2.85 g) inN,N-dimethylformamide under ice-cooling. The mixture was stirred at thesame temperature for 15 min, 4-fluorobenzenesulfonyl chloride (2.92 g)was added, and the mixture was stirred at room temperature for 3 hr.Water was added to the reaction mixture, and the mixture was extractedwith diethyl ether. The extract was washed with saturated brine, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=4:1) to give the title compound ascrystals (yield 4.66 g, 97%).

¹H-NMR (CDCl₃) δ: 1.36 (3H, t, J=7.2 Hz), 4.31 (2H, q, J=7.2 Hz), 6.53(1H, d, J=1.9 Hz), 6.96-7.06 (4H, m), 7.16-7.24 (2H, m), 7.36-7.45 (2H,m), 8.06 (1H, d, J=1.9 Hz).

Reference Example 30 Ethyl5-(4-fluorophenyl)-1-{[4-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrole-3-carboxylate

Using 4-fluorophenacyl bromide instead of phenacyl bromide, a procedureas in Reference Example 1 was performed to synthesize ethyl2-cyano-4-(4-fluorophenyl)-4-oxobutanoate, and procedures as inReference Examples 2 and 3 were performed to synthesize ethyl5-(4-fluorophenyl)-1H-pyrrole-3-carboxylate. Sodium hydride (60% in oil,0.28 g) was added to a solution (20 mL) of ethyl5-(4-fluorophenyl)-1H-pyrrole-3-carboxylate (1.49 g) inN,N-dimethylformamide under ice-cooling. The mixture was stirred at thesame temperature for 15 min, 4-trifluoromethylbenzenesulfonyl chloride(1.85 g) was added, and the mixture was stirred at room temperature for3 hr. Water was added to the reaction mixture, and the mixture wasextracted with diethyl ether. The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=7:2) to give the titlecompound as crystals (yield 1.80 g, 64%).

¹H-NMR (CDCl₃) δ: 1.36 (3H, t, J=7.1 Hz), 4.32 (2H, q, J=7.1 Hz), 6.55(1H, d, J=1.9 Hz), 7.01 (2H, t, J=8.8 Hz), 7.11-7.18 (2H, m), 7.47 (2H,d, J=8.3 Hz), 7.62 (2H, d, J=8.3 Hz), 8.07 (1H, d, J=1.9 Hz).

Reference Example 315-(4-Fluorophenyl)-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde

Using ethyl5-(4-fluorophenyl)-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate,procedures as in Reference Examples 5 and 6 were performed to give thetitle compound as an oil.

¹H-NMR (CDCl₃) δ: 6.55 (1H, d, J=1.9 Hz), 6.98 (2H, t, J=8.8 Hz),7.08-7.18 (2H, m), 7.33-7.40 (4H, m), 7.51-7.63 (1H, m), 8.12 (1H, d,J=1.9 Hz), 9.88 (1H, s).

Reference Example 325-(2-Methylphenyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole-3-carbaldehyde

Using ethyl 2-cyano-4-(2-methylphenyl)-4-oxobutanoate, a procedure as inReference Example 2 was performed to synthesize ethyl2-chloro-5-(2-methylphenyl)-1H-pyrrole-3-carboxylate, and procedures asin Reference Examples 3, 4, 5 and 6 were sequentially performed to givethe title compound as crystals.

¹H-NMR (CDCl₃) δ: 1.80 (3H, s), 2.41 (3H, s), 6.50 (1H, s), 6.90 (1H, d,J=6.2 Hz), 7.07-7.35 (7H, m), 8.12 (1H, s), 9.89 (1H, s).

Reference Example 331-[(4-Fluorophenyl)sulfonyl]-5-(4-methoxyphenyl)-1H-pyrrole-3-carbaldehyde

Using ethyl 5-(4-methoxyphenyl)-1H-pyrrole-3-carboxylate and4-fluorobenzenesulfonyl chloride, a procedure as in Reference Example 4was performed to synthesize ethyl1-[(4-fluorophenyl)sulfonyl]-5-(4-methoxyphenyl)-1H-pyrrole-3-carboxylate,and procedures as in Reference Examples 5 and 6 were sequentiallyperformed to give the title compound as an oil.

¹H-NMR (CDCl₃) δ: 3.86 (3H, s), 6.52 (1H, d, J=1.9 Hz), 6.84 (2H, d,J=8.7 Hz), 7.01 (2H, t, J=8.7 Hz), 7.09 (2H, d, J=8.7 Hz), 7.34 (2H, dd,J=8.9 Hz, 4.9 Hz), 8.08 (1H, d, J=1.9 Hz), 9.87 (1H, s).

Reference Example 345-(4-Fluorophenyl)-1-[(4-fluorophenyl)sulfonyl]-1H-pyrrole-3-carbaldehyde

Using ethyl5-(4-fluorophenyl)-1-[(4-fluorophenyl)sulfonyl]-1H-pyrrole-3-carboxylate,procedures as in Reference Examples 5 and 6 were performed to give thetitle compound as a solid.

¹H-NMR (CDCl₃) δ: 6.57 (1H, d, J=1.8 Hz), 6.97-7.08 (4H, m), 7.12-7.18(2H, m), 7.32-7.39 (2H, m), 8.10 (1H, d, J=1.8 Hz), 9.88 (1H, s).

Reference Example 355-(4-Fluorophenyl)-1-{[4-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrole-3-carbaldehyde

Using ethyl5-(4-fluorophenyl)-1-{[4-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrole-3-carboxylate,procedures as in Reference Examples 5 and 6 were performed to give thetitle compound as crystals.

¹H-NMR (CDCl₃) δ: 6.59 (1H, d, J=1.7 Hz), 7.02 (2H, t, J=8.7 Hz),7.11-7.17 (2H, m), 7.47 (2H, d, J=8.5 Hz), 7.63 (2H, d, J=8.5 Hz), 8.11(1H, d, J=1.9 Hz), 9.89 (1H, s).

Reference Example 361-[(4-Fluorophenyl)sulfonyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbaldehyde

Using ethyl 5-(2-trifluoromethylphenyl)-1H-pyrrole-3-carboxylate and4-fluorobenzenesulfonyl chloride, a procedure as in Reference Example 4was performed to synthesize ethyl1-[(4-fluorophenyl)sulfonyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate,and procedures as in Reference Examples 5 and 6 were sequentiallyperformed to give the title compound as crystals.

¹H-NMR (CDCl₃) δ: 6.65 (1H, s), 7.00-7.09 (2H, m), 7.33-7.46 (3H, m),7.57-7.67 (3H, m), 8.13 (1H, d, J=1.9 Hz), 9.89 (1H, s).

Reference Example 371-[(4-Methylphenyl)sulfonyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbaldehyde

Using ethyl 2-cyano-4-oxo-4-(2-trifluoromethylphenyl)butanoate, aprocedure as in Reference Example 2 was performed to synthesize ethyl2-chloro-5-(2-trifluoromethylphenyl)-1H-pyrrole-3-carboxylate, andprocedures as in Reference Examples 3, 4, 5 and 6 were sequentiallyperformed to give the title compound as crystals.

¹H-NMR (CDCl₃) δ: 2.40 (3H, s), 6.63 (1H, d, J=1.7 Hz), 7.16 (2H, d,J=8.3 Hz), 7.25 (2H, d, J=8.3 Hz), 7.36-7.42 (1H, m), 7.53-7.64 (3H, m),8.12 (1H, d, J=1.9 Hz), 9.88 (1H, s).

Reference Example 382-Methyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde

Using ethyl 2-methyl-5-phenyl-1H-pyrrole-3-carboxylate andbenzenesulfonyl chloride, a procedure as in Reference Example 4 wasperformed to synthesize ethyl2-methyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate, andprocedures as in Reference Examples 5 and 6 were sequentially performedto give the title compound as a colorless oil.

¹H-NMR (CDCl₃) δ: 2.88 (3H, s), 6.47 (1H, s), 7.18-7.23 (2H, m),7.48-7.61 (1H, m), 10.00 (1H, s).

Reference Example 39 Methyl 1H-pyrrole-3-carboxylate

A solution (250 mL) of p-toluenesulfonylmethyl isocyanide (15.0 g) andmethyl acrylate (6.92 mL) in tetrahydrofuran was added dropwise to asuspension (100 mL) of potassium tert-butoxide in tetrahydrofuran over30 min. The reaction mixture was stirred at room temperature for 1 hr,and filtered through a glass filter filled with silica gel (diameter 8cm, height 4 cm), and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=9:1→2:1) to give the title compound as apale-yellow solid (yield 4.69 g, 49%).

¹H-NMR (CDCl₃) δ: 3.82 (3H, s), 6.15 (1H, m), 6.75 (1H, m), 7.43 (1H,m), 8.50 (1H, brs).

Reference Example 40 Methyl 5-bromo-1H-pyrrole-3-carboxylate

A solution (70 mL) of methyl 1H-pyrrole-3-carboxylate (4.48 g) intetrahydrofuran was cooled to −78° C., N-bromosuccinimide (6.30 g) wasadded, pyridine (5 drops) was added, and the mixture was left standingin a freezer (−20° C.) for 3 days. The reaction mixture was concentratedunder reduced pressure, water was added to the residue and the mixturewas extracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=9:1→1:1) to give the titlecompound as a pale-yellow solid (yield 3.59 g, 49%).

¹H-NMR (CDCl₃) δ: 3.81 (3H, s), 6.58 (1H, m), 7.36 (1H, m), 8.60 (1H,brs).

Reference Example 41 Methyl5-bromo-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrrole-3-carboxylate

Sodium hydride (60% in oil, 681 mg) was washed with hexane, and added toN,N-dimethylformamide (10 mL). After cooling to −78° C., a solution (10mL) of methyl 5-bromo-1H-pyrrole-3-carboxylate (2.90 g) inN,N-dimethylformamide was added dropwise over 15 min. The reactionmixture was stirred at 0° C. for 30 min and at 25° C. for 30 min, andagain cooled to −78° C. A solution (5 mL) of 4-methoxybenzenesulfonylchloride (3.23 g) in N,N-dimethylformamide was added dropwise, and thereaction mixture was stirred at 0° C. for 15 min and at 25° C. for 30min. The reaction mixture was concentrated under reduced pressure, waterwas added to the residue, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by basic silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→1:1) to give the title compound as a colorlesssolid (yield 3.02 g, 57%).

¹H-NMR (CDCl₃) δ: 3.82 (3H, s), 3.88 (3H, s), 6.65 (1H, d, J=2.0 Hz),7.00 (2H, d, J=9.2 Hz), 7.92 (2H, d, J=9.2 Hz), 8.05 (1H, d, J=2.0 Hz).

Reference Example 425-Bromo-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrrole-3-carbaldehyde

A solution (30 mL) of methyl5-bromo-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrrole-3-carboxylate (3.00 g)in tetrahydrofuran was cooled to −78° C., a 1.5 mol/l solution (11.0 mL)of diisobutylaluminum hydride in toluene was added dropwise over 15 min,and the mixture was further stirred at −78° C. for 1 hr. A 1.5 mol/lsolution (5.0 mL) of diisobutylaluminum hydride in toluene was added,and the mixture was stirred at −78° C. for 15 min, and at 25° C. for 2hr. 1 mol/l Hydrochloric acid (40 mL) was added to the reaction mixture,and the mixture was stirred at 25° C. for 15 min and extracted withethyl acetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Asolution (30 mL) of the residue in acetonitrile was cooled to 0° C.,tetra-n-propylammonium perruthenate (281 mg), N-methylmorpholine N-oxide(1.41 g) and molecular sieves 4A powder (1.5 g) were added, and themixture was stirred at room temperature for 1.5 hr. The reaction mixturewas concentrated under reduced pressure, and the residue was suspendedin ethyl acetate and filtered through celite. The filtrate wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent: hexane-ethyl acetate=9:1→1:1)to give the title compound as a brown oil (yield 2.07 g, 75%).

¹H-NMR (CDCl₃) δ: 3.90 (3H, s), 6.71 (1H, d, J=2.2 Hz), 7.02 (2H, d,J=9.2 Hz), 7.94 (2H, d, J=9.2 Hz), 8.07 (1H, d, J=2.2 Hz), 9.75 (1H, s).

Reference Example 43 tert-Butyl({5-bromo-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate

To a solution (90 mL) of5-bromo-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrrole-3-carbaldehyde (3.0 g)in methanol was added methylammonium chloride (5.88 g), and the mixturewas stirred at room temperature for 15 min. Sodium cyanotrihydroborate(1.64 g) was added, and the mixture was further stirred at roomtemperature for 2 hr. The reaction mixture was concentrated underreduced pressure, saturated aqueous sodium hydrogen carbonate was addedto the residue and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous sodiumsulfate, and filtered. To the filtrate was added di-tert-butylbicarbonate (2.28 g), and the mixture was concentrated under reducedpressure. The residue was dissolved in tetrahydrofuran (10 mL), sodiumhydrogencarbonate (1.10 g) and water (10 mL) were added, and the mixturewas stirred at room temperature for 15 min. Water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=9:1→1:1) to give the title compound as a pale-yellow oil (yield2.25 g, 56%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.78 (3H, s), 3.87 (3H, s), 4.16 (2H,s), 6.22 (1H, s), 6.97 (2H, d, J=9.2 Hz), 7.33 (1H, s), 7.86 (2H, d,J=9.2 Hz).

Reference Example 444-(Azidomethyl)-1-[(4-methylphenyl)sulfonyl]-2-phenyl-1H-pyrrole

A solution (10 mL) of ethyl1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate (500 mg)in tetrahydrofuran was cooled to −78° C., a 1.5 mol/l solution (2.70 mL)of diisobutylaluminum hydride in toluene was added dropwise, and themixture was stirred at 25° C. for 30 min. 1 mol/l Hydrochloric acid (6mL) was added to the reaction mixture, and the mixture was stirred at25° C. for 15 min and extracted with ethyl acetate. The extract waswashed with saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. A solution (2 mL) of the residue indichloromethane was added to a solution (5 mL) of2,3-dichloro-5,6-dicyano-1,4-benzoquinone (612 mg), triphenylphosphine(532 mg) and tetra-n-butylammoniumazide (768 mg) in tetrahydrofuran, andthe mixture was stirred at 25° C. for 1 hr. The reaction mixture wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent: hexane-ethyl acetate=9:1→1:1)to give the title compound as a pale-yellow solid (yield 233 mg, 49%).

¹H-NMR (CDCl₃) δ: 2.36 (3H, s), 4.48 (2H, s), 6.19 (1H, d, J=2.2 Hz),7.09 (2H, d, J=8.6 Hz), 7.15-7.40 (8H, m).

Reference Example 45 Ethyl 4-methyl-1H-pyrrole-3-carboxylate

Using p-toluenesulfonylmethyl isocyanide (8.55 g), ethyl crotonate (5.0g) and potassium tert-butoxide (5.90 g), a procedure as in ReferenceExample 39 was performed to give the title compound as a pale-yellowsolid (yield 4.77 g, 71%).

¹H-NMR (CDCl₃) δ: 1.34 (3H, t, J=6.8 Hz), 2.29 (3H, s), 4.27 (2H, q,J=6.8 Hz), 6.53 (1H, m), 7.38 (1H, m), 8.30 (1H, brs).

Reference Example 46 Ethyl 5-bromo-4-methyl-1H-pyrrole-3-carboxylate

Using ethyl 4-methyl-1H-pyrrole-3-carboxylate (4.50 g) andN-bromosuccinimide (5.2 g), a procedure as in Reference Example 40 wasperformed to give the title compound as a pale-yellow solid (yield 5.20g, 76%).

¹H-NMR (CDCl₃) δ: 1.34 (3H, t, J=7.4 Hz), 2.23 (3H, s), 4.27 (2H, q,J=7.4 Hz), 7.38 (1H, d, J=3.0 Hz), 8.30 (1H, brs).

Reference Example 47 Ethyl5-bromo-4-methyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole-3-carboxylate

Using sodium hydride (60% in oil, 620 mg), ethyl5-bromo-4-methyl-1H-pyrrole-3-carboxylate (3.0 g) and tosyl chloride(2.95 g), a procedure as in Reference Example 41 was performed to givethe title compound as pale-yellow crystals (yield 4.27 g, 86%).

¹H-NMR (CDCl₃) δ: 1.35 (3H, t, J=7.0 Hz), 2.15 (3H, s), 2.44 (3H, s),4.29 (2H, q, J=7.0 Hz), 7.34 (2H, d, J=7.6 Hz), 7.84 (2H, d, J=7.6 Hz),8.09 (1H, s).

Reference Example 48 Ethyl4-methyl-1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate

Ethyl5-bromo-4-methyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole-3-carboxylate(1.0 g), phenylboronic acid (473 mg), sodium carbonate (823 mg) andtetrakis(triphenylphosphine)palladium (299 mg) were suspended in amixture of 1,2-dimethoxyethane (10 mL) and distilled water (10 mL), andthe mixture was refluxed under a nitrogen atmosphere for 16 hr. Thereaction mixture was filtrated, water was added to the filtrate and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=9:1→1:1) to give the titlecompound as a pale-brown oil (yield 430 mg, 42%).

¹H-NMR (CDCl₃) δ: 1.37 (3H, t, J=7.0 Hz), 1.98 (3H, s), 2.37 (3H, s),4.31 (2H, q, J=7.0 Hz), 6.95-7.40 (9H, m), 8.06 (1H, s).

Reference Example 494-Methyl-1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde

A solution of (10 mL) ethyl4-methyl-1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate(420 mg) in tetrahydrofuran was cooled to −78° C., a 1.5 mol/l solution(2.1 mL) of diisobutylaluminum hydride in toluene was added dropwise,and the mixture was further stirred at −78° C. for 30 min. 1 mol/lHydrochloric acid (10 mL) was added to the reaction mixture, and themixture was stirred at room temperature and extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Asolution (15 mL) of the residue in acetonitrile was cooled to −78° C.,tetra-n-propylammonium perruthenate (37 mg), N-methylmorpholine N-oxide(185 mg) and molecular sieves 4A powder (1.0 g) were added, and themixture was stirred at room temperature for 1 hr. The reaction mixturewas concentrated under reduced pressure, and the residue was suspendedin ethyl acetate and filtered through celite. The filtrate wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent: hexane-ethyl acetate=9:1→1:1)to give the title compound as a brown oil (yield 320 mg, 90%).

¹H-NMR (CDCl₃) δ: 2.02 (3H, s), 2.38 (3H, s), 6.99-7.40 (9H, m), 8.04(1H, s), 9.95 (1H, s).

Reference Example 50 tert-Butyl({5-bromo-1-[(4-methylphenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate

Using methyl 5-bromo-1H-pyrrole-3-carboxylate and tosyl chloride, aprocedure as in Reference Example 41 was performed to synthesize methyl5-bromo-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole-3-carboxylate, andprocedures as in Reference Examples 42 and 43 were sequentiallyperformed to give the title compound as a colorless solid.

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.43 (3H, s), 2.78 (3H, s), 4.17 (2H,s), 6.23 (1H, s), 7.25-7.35 (3H, m), 7.80 (2H, d, J=8.4 Hz).

Reference Example 51 Methyl5-bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate

Sodium hydride (60% in oil, 1.1 g) was washed with hexane and added toN,N-dimethylformamide (50 mL). The mixture was cooled to 0° C., and asolution (10 mL) of methyl 5-bromo-1H-pyrrole-3-carboxylate (5.0 g) inN,N-dimethylformamide was added. After stirring at 0° C. for 30 min, asolution (5 mL) of benzenesulfonyl chloride (3.3 mL) inN,N-dimethylformamide was added. The reaction mixture was stirred atroom temperature for 1 hr, water was added, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedaqueous sodium hydrogen carbonate, water and saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=5:1) to give the title compound as a colorlesssolid (yield 8.5 g, 99%).

¹H-NMR (CDCl₃) δ: 3.83 (3H, s), 6.68 (1H, d, J=2.1 Hz), 7.55-7.60 (2H,m), 7.67-7.72 (1H, m), 7.96-7.99 (2H, m), 8.08 (1H, d, J=2.1 Hz).

Reference Example 52 [5-Bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol

A solution (80 mL) of methyl5-bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (7.1 g) intetrahydrofuran was cooled to −78° C., a 1.5 mol/l solution (42 mL) ofdiisobutylaluminum hydride in toluene was added dropwise over 30 min,and the mixture was further stirred at −78° C. for 1 hr. 1 mol/lHydrochloric acid (20 mL) was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed withsaturated aqueous sodium hydrogen carbonate, water, saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure to give the title compound as a brown oil (yield 7.1 g,quantitative).

¹H-NMR (CDCl₃) δ: 1.62 (1H, brs), 4.51 (2H, s), 6.33-6.34 (1H, m),7.44-7.45 (1H, m), 7.51-7.57 (2H, m), 7.62-7.68 (1H, m), 7.93-7.97 (2H,m).

Reference Example 535-Bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde

To a solution (80 mL) of[5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol (7.1 g) inacetonitrile were added tetra-n-propylammonium perruthenate (0.63 g),N-methylmorpholine N-oxide hydrate (4.2 g) and molecular sieves 4Apowder (3.5 g) and the mixture was stirred at room temperature for 2 hr.The reaction mixture was concentrated under reduced pressure, water wasadded to the residue, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=4:1) to give the title compound as a colorless solid (yield 4.6g, 71%).

¹H-NMR (CDCl₃) δ: 6.73 (1H, d, J=2.1 Hz), 7.57-7.63 (2H, m), 7.70-7.75(1H, m), 7.98-8.02 (2H, m), 8.10 (1H, d, J=2.1 Hz), 9.77 (1H, s).

Reference Example 541-[5-Bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine

To a solution (60 mL) of5-bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (3.5 g) in methanolwere added methylammonium chloride (7.5 g) and sodium cyanoborohydride(2.4 g), and the mixture was stirred at room temperature for 1 hr. Thereaction mixture was concentrated under reduced pressure. Saturatedaqueous sodium hydrogen carbonate was added to the residue, and themixture was extracted with ethyl acetate. The extract was washed withsaturated aqueous sodium hydrogen carbonate, water and saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure to give the title compound as a brown oil (yield 4.4 g,quantitative).

¹H-NMR (CDCl₃) δ: 2.47 (3H, s), 2.98 (1H, brs), 3.66 (2H, s), 6.35 (1H,d, J=2.4 Hz), 7.51-7.57 (3H, m), 7.61-7.68 (1H, m), 7.93-7.97 (2H, m).

Reference Example 55 tert-Butyl{[5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

To a solution of1-[5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (4.4g) in ethyl acetate (60 mL) was added di-tert-butyl bicarbonate (2.8mL), and the mixture was stirred at room temperature for 14 hr.Saturated aqueous sodium hydrogen carbonate was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas washed with aqueous sodium hydrogencarbonate solution and saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=4:1) to give the titlecompound as a colorless oil (yield 3.4 g, 73%).

¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 2.79 (3H, brs), 4.17 (2H, brs), 6.24(1H, brs), 7.35 (1H, brs), 7.51-7.57 (2H, m), 7.62-7.68 (1H, m),7.90-7.94 (2H, m).

Reference Example 56 tert-Butylmethyl{[1-(phenylsulfonyl)-5-(3-thienyl)-1H-pyrrol-3-yl]methyl}carbamate

A suspension of tert-butyl{[5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (1.02g), 3-thienylboronic acid (0.61 g),tetrakis(triphenylphosphine)palladium (0.41 g) and sodium carbonate(0.75 g) in 1,2-dimethoxyethane (25 mL)-water (25 mL) was stirred at105° C. for 7 hr. After cooling, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedaqueous sodium hydrogen carbonate, water and saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1) to give the title compound as a colorlesssolid (yield 0.90 g, 88%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.81 (3H, brs), 4.21 (2H, brs), 6.13(1H, brs), 7.04 (1H, dd, J=1.2, 3.0 Hz), 7.11 (1H, dd, J=1.2, 3.0 Hz),7.24 (1H, dd, J=3.0, 5.1 Hz), 7.30-7.39 (5H, m), 7.48-7.54 (1H, m).

Reference Example 57 tert-Butylmethyl{[5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate

A suspension of tert-butyl{[5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (1.04g), phenylboronic acid (0.45 g), tetrakis(triphenylphosphine)palladium(0.42 g) and sodium carbonate (0.77 g) in 1,2-dimethoxyethane (25mL)-water (25 mL) was stirred at 105° C. for 12 hr. After cooling,saturated aqueous sodium hydrogen carbonate was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated aqueous sodium hydrogen carbonate, water andsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=4:1) to give thetitle compound as a colorless solid (yield 0.97 g, 94%).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.80 (3H, brs), 4.22 (2H, brs), 6.09(1H, brs), 7.19-7.23 (2H, m), 7.26-7.38 (8H, m), 7.47-7.53 (1H, m).

Reference Example 58 tert-Butyl{{5-bromo-1-[(4-fluorophenyl)sulfonyl]-1H-pyrrol-3-yl}methyl}methylcarbamate

Using methyl 5-bromo-1H-pyrrole-3-carboxylate and4-fluorobenzenesulfonyl chloride, a procedure as in Reference Example 55was performed to synthesize methyl5-bromo-1-[(4-fluorophenyl)sulfonyl]-1H-pyrrole-3-carboxylate, andprocedures as in Reference Examples 52, 53, 54 and 55 were sequentiallyperformed to give the title compound as a colorless oil.

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.79 (3H, brs), 4.17 (2H, brs), 6.25(1H, brs), 7.19-7.25 (2H, m), 7.33 (1H, brs), 7.93-7.98 (2H, m).

Reference Example 59 tert-Butyl{{1-[(4-fluorophenyl)sulfonyl]-5-(3-thienyl)-1H-pyrrol-3-yl}methyl}methylcarbamate

Using tert-butyl{{5-bromo-1-[(4-fluorophenyl)sulfonyl]-1H-pyrrol-3-yl}methyl}methylcarbamate(0.60 g), 3-thienylboronic acid (0.35 g),tetrakis(triphenylphosphine)palladium (0.24 g) and sodium carbonate(0.43 g), a procedure as in Reference Example 56 was performed to givethe title compound as a colorless solid (yield 0.42 g, 69%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.81 (3H, brs), 4.22 (2H, brs), 6.14(1H, brs), 6.97-7.06 (3H, m), 7.14-7.15 (1H, m), 7.25-7.31 (2H, m),7.34-7.39 (2H, m).

Reference Example 60 tert-Butyl{{5-bromo-1-[(3-chlorophenyl)sulfonyl]-1H-pyrrol-3-yl}methyl}methylcarbamate

Using methyl 5-bromo-1H-pyrrole-3-carboxylate and3-chlorobenzenesulfonyl chloride, a procedure as in Reference Example 55was performed to synthesize methyl5-bromo-1-[(3-chlorophenyl)sulfonyl]-1H-pyrrole-3-carboxylate, andprocedures as in Reference Examples 52, 53, 54 and 55 were sequentiallyperformed to give the title compound as a pale-yellow oil.

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.80 (3H, brs), 4.18 (2H, brs), 6.26(1H, brs), 7.33 (1H, brs), 7.46-7.51 (1H, m), 7.60-7.63 (1H, m),7.80-7.82 (1H, m), 7.89-7.90 (1H, m).

Reference Example 61 tert-Butyl{{1-[(3-chlorophenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl}methylcarbamate

Using tert-butyl{{5-bromo-1-[(3-chlorophenyl)sulfonyl]-1H-pyrrol-3-yl}methyl}methylcarbamate(1 g), phenylboronic acid (526 mg), sodium carbonate (687 mg) andtetrakis(triphenylphosphine)palladium (374 mg), a procedure as inReference Example 57 was performed to give the title compound as apale-yellow oil (yield 726 mg, 73%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.81 (3H, brs), 4.81 (2H, brs), 6.11(1H, brs), 7.19-7.49 (10H, m).

Reference Example 62 tert-Butyl{{1-[(3-chlorophenyl)sulfonyl]-5-(3-thienyl)-1H-pyrrol-3-yl}methyl}methylcarbamate

Using tert-butyl({5-bromo-1-[(3-chlorophenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate(1 g), 3-thienylboronic acid (553 mg), sodium carbonate (687 mg) andtetrakis(triphenylphosphine)palladium (374 mg), a procedure as inReference Example 56 was performed to give the title compound as apale-yellow oil (yield 712 mg, 71%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.82 (3H, brs), 4.22 (2H, brs), 6.16(1H, brs), 7.03-7.05 (1H, m), 7.14-7.16 (1H, m), 7.23-7.31 (5H, m),7.45-7.49 (1H, m).

Reference Example 63 tert-Butyl{{1-[(3-chlorophenyl)sulfonyl]-5-(4-fluorophenyl)-1H-pyrrol-3-yl}methyl}methylcarbamate

Using tert-butyl{{5-bromo-1-[(3-chlorophenyl)sulfonyl]-1H-pyrrol-3-yl}methyl}methylcarbamate(1 g), (4-fluorophenyl)boronic acid (628 mg), sodium carbonate (708 mg)and tetrakis(triphenylphosphine)palladium (388 mg), a procedure as inReference Example 56 was performed to give the title compound as apale-yellow oil (yield 930 mg, 87%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.80 (3H, s), 4.22 (2H, brs), 6.09 (1H,brs), 6.91-7.50 (9H, m).

Reference Example 64 (5-Phenyl-1H-pyrrol-3-yl)methanol

A solution (100 mL) of ethyl 5-phenyl-1H-pyrrole-3-carboxylate (2.16 g)in tetrahydrofuran was cooled to −78° C., and a 1.5 mol/L solution (24mL) of diisobutylaluminum hydride in toluene was added dropwise over 10min. The mixture was further stirred at −78° C. for 1 hr, water (2 mL)was added dropwise over 2 min, and the mixture was further stirred atroom temperature for 1 hr. To the reaction mixture were added celite andanhydrous magnesium sulfate, the mixture was filtered and the filtratewas concentrated under reduced pressure to give the title compound as apale-red powder (yield 1.51 g, 87%).

¹H-NMR (DMSO-d₆) δ: 4.34 (2H, d, J=5.4 Hz), 4.60 (1H, t, J=5.4 Hz),6.45-6.46 (1H, m), 6.74 (1H, br), 7.11-7.15 (1H, m), 7.31-7.35 (2H, m),7.57-7.59 (2H, m), 11.05 (1H, s).

Reference Example 65 5-Phenyl-1H-pyrrole-3-carbaldehyde

To a solution (45 mL) of (5-phenyl-1H-pyrrol-3-yl)methanol (1.51 g) inacetonitrile were added tetra-n-propylammonium perruthenate (0.46 g),N-methylmorpholine N-oxide (2.36 g) and molecular sieves 4A powder (4.5g), and the mixture was stirred at room temperature for 1.5 hr. Thereaction mixture was filtered through celite, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=4:1→1:1) to givethe title compound as a pale-yellow powder (yield 0.92 g, 62%).

¹H-NMR (CDCl₃) δ: 6.95 (1H, m), 7.29-7.32 (1H, m), 7.40-7.44 (2H, m),7.50-7.52 (3H, m), 9.02 (1H, br), 9.84 (1H, s).

Reference Example 66 tert-Butylmethyl[(5-phenyl-1H-pyrrol-3-yl)methyl]carbamate

To a solution (92 mL) of 5-phenyl-1H-pyrrole-3-carbaldehyde (0.92 g) inmethanol was added 40% methylamine solution (1.26 g) at room temperatureand the mixture was stirred for 30 min. To the reaction mixture wasadded sodium borohydride (305 mg) at room temperature and the mixturewas stirred for 10 min. Water (200 mL) was added and the mixture wasfurther stirred for 1 hr. Saturated brine (50 mL) was added and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was dissolved in acetonitrile (48mL), and di-tert-butyl bicarbonate (1.41 g) was added dropwise at roomtemperature. The mixture was stirred for 1.5 hr and partitioned withwater and ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=9:1→4:1) to give the titlecompound as colorless crystals (yield 0.99 g, 64%).

¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 2.84 (3H, s), 4.30 (2H, s), 6.45 (1H,s), 6.75 (1H, s), 7.18-7.22 (1H, m), 7.34-7.38 (2H, m), 7.44-7.46 (2H,m), 8.37 (1H, br).

Reference Example 67 2-Bromo-1-(2-fluorophenyl)propan-1-one

To a solution of 2′-fluoropropiophenone (25.0 g) in acetic acid (250 mL)was slowly added bromine (8.4 mL). The mixture was stirred at roomtemperature for 3 hr, and concentrated under reduced pressure. To theresidue was added water (200 mL), and the mixture was extracted withdiisopropyl ether. The extract was washed with saturated aqueous sodiumhydrogencarbonate solution, water and saturated brine, dried overanhydrous magnesium sulfate, and filtrated. The filtrate wasconcentrated under reduced pressure to give the title compound as ayellow oil (yield 36.8 g, 97%).

¹H-NMR (CDCl₃) δ: 1.89-1.91 (3H, m), 5.27-5.34 (1H, m), 7.12-7.19 (1H,m), 7.24-7.30 (1H, m), 7.52-7.59 (1H, m), 7.88-7.93 (1H, m).

Reference Example 68 2-Bromo-1-(3-thienyl)ethanone

To a solution of 3-acetylthiophene (3.73 g) in diethyl ether (60 mL) wasadded aluminum chloride (386 mg), and the mixture was stirred for 5 min.Bromine (1.55 mL) was slowly added at room temperature to this mixture,and the mixture was further stirred for 2 hr. Aqueous sodium carbonatesolution was added to the reaction mixture, and the mixture wasextracted with diethyl ether. The extract was dried over anhydroussodium sulfate, filtrated, and concentrated under reduced pressure. Theresidue was recrystallized from diisopropyl ether to give the titlecompound as white crystals (yield 3.93 g, 65%).

¹H-NMR (CDCl₃) δ: 4.34 (2H, s), 7.35-7.38 (1H, m), 7.57-7.60 (1H, m),8.17-8.19 (1H, m).

Reference Example 69 Ethyl 2-cyano-4-(2-fluorophenyl)-4-oxobutanoate

To a solution of 2′-fluoroacetophenone (28.6 g) in ethyl acetate (400mL), copper (II) bromide (92.6 g) was added, and the mixture was heatedunder reflux for 4 hr. The reaction mixture was cooled to roomtemperature and the insoluble material was filtered off. The filtratewas concentrated under reduced pressure to give crude1-bromo-1-(2-fluorophenyl)ethanone (yield 90.5 g) as an oil. Potassiumcarbonate (88 g) was added to ethyl cyanoacetate (168 g), and themixture was stirred at 45° C. for 1 hr. A solution (360 mL) of crude1-bromo-1-(2-fluorophenyl)ethanone (90.5 g) in acetone was addeddropwise over 20 min. After completion of the dropwise addition, themixture was stirred at the same temperature for 1 hr. To the reactionmixture water (300 mL) and ethyl acetate (300 mL) were added, and themixture was extracted with ethyl acetate. The extract was washed with10% aqueous sodium dihydrogenphosphate solution and saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. An excess ethyl cyanoacetate contained in the obtained oil wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent: hexane-ethyl acetate=20:1→4:1)to give the title compound as an oil (yield 64.0 g, about 100%).

¹H-NMR (CDCl₃) δ: 1.35 (3H, t, J=7.2 Hz), 3.55-3.80 (2H, m), 4.11 (1H,t, J=6.0 Hz), 4.24-4.34 (2H, m), 7.15-7.29 (2H, m), 7.55-7.62 (1H, m),7.94 (1H, dt, J=1.8, 7.5 Hz).

Reference Example 70 Methyl2-cyano-4-(2-fluorophenyl)-3-methyl-4-oxobutanoate

To a solution of methyl cyanoacetate (15.5 mL) and diisopropylethylamine(64 mL) in tetrahydrofuran (110 mL) was added a solution of2-bromo-1-(2-fluorophenyl)propan-1-one (36.8 g) in tetrahydrofuran (160mL), and the mixture was stirred at 70° C. for 20 hr. The reactionmixture was allowed to cool to room temperature, the insoluble materialwas filtered off, and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=5:1) to give the title compound as a brownoil (yield 31.9 g, 80%).

¹H-NMR (CDCl₃) δ: 1.42-1.46 (3H, m), 3.82-3.85 (4H, m), 3.99-4.17 (1H,m), 7.14-7.22 (1H, m), 7.25-7.31 (1H, m), 7.55-7.63 (1H, m), 7.85-7.91(1H, m).

Reference Example 71 Ethyl 2-acetyl-3-methyl-4-oxo-4-phenylbutanoate

Using ethyl 3-oxobutanoate (12.2 g), sodium hydride (60% in oil, 4.24 g)and 2-bromopropiophenone (22.0 g), a procedure as in Reference Example13 was performed to give the title compound as a brown oil (yield 22.1g, 90%).

¹H-NMR (CDCl₃) δ: 1.13-1.21 (3H, m), 1.31-1.36 (3H, m), 2.31-2.41 (3H,m), 4.04-4.31 (4H, m), 7.45-7.51 (2H, m), 7.55-7.61 (1H, m), 7.98-8.03(2H, m).

Reference Example 72 Ethyl2-acetyl-3-methyl-4-oxo-4-(3-thienyl)butanoate

Using ethyl 3-oxobutanoate (2.40 g), sodium hydride (60% in oil, 803 mg)and 2-bromo-1-(3-thienyl)ethanone (3.80 g), a procedure as in ReferenceExample 13 was performed to give the title, compound as a brown oil(yield 1.87 g, 40%).

¹H-NMR (CDCl₃) δ: 1.27-1.32 (3H, m), 2.43 (3H, s), 3.39-3.48 (1H, m),3.59-3.68 (1H, m), 4.18-4.26 (3H, m), 7.31-7.34 (1H, m), 7.53-7.55 (1H,m), 8.12-8.14 (1H, m).

Reference Example 73 Ethyl2-chloro-5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate

A mixture of ethyl 2-cyano-4-(2-fluorophenyl)-4-oxobutanoate (19.3 g)and 4 mol/L hydrogen chloride-ethyl acetate solution (100 mL) wasstirred at room temperature for 18 hr. The reaction mixture wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent: hexane-ethyl acetate=10:1→3:1)to give the title compound as a brown solid (yield 8.76 g, 53%).

¹H-NMR (CDCl₃) δ: 1.36-1.41 (3H, m), 4.33 (2H, q, J=7.2 Hz), 6.99-7.00(1H, m), 7.09-7.26 (3H, m), 7.55-7.61 (1H, m), 9.08 (1H, brs).

Reference Example 74 Methyl2-chloro-5-(2-fluorophenyl)-4-methyl-1H-pyrrole-3-carboxylate

To a solution of methyl2-cyano-4-(2-fluorophenyl)-3-methyl-4-oxobutanoate (31.0 g) in ethylacetate (30 mL) was added 4 mol/L hydrogen chloride-ethyl acetatesolution (150 mL), and the mixture was stirred at room temperature for 2days. To the reaction mixture was added water (200 mL), and the mixturewas extracted with ethyl acetate. The extract was washed with water(twice) and saturated aqueous sodium hydrogencarbonate solution, driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The residue was recrystallized from ethyl acetate to give thetitle compound as white crystals (yield 19.3 g, 58%).

¹H-NMR (CDCl₃) δ: 2.33 (3H, s), 3.86 (3H, s), 7.12-7.42 (4H, m), 8.53(1H, brs).

Reference Example 75 Ethyl2,4-dimethyl-5-phenyl-1H-pyrrole-3-carboxylate

Using ethyl 2-acetyl-3-methyl-4-oxo-4-phenylbutanoate (20.3 g) andammonium acetate (6.61 g), a procedure as in Reference Example 14 wasperformed to give the title compound as a brown oil (yield 17.1 g, 91%).

¹H-NMR (CDCl₃) δ: 1.36 (3H, t, J=7.2 Hz), 2.38 (3H, s), 2.54 (3H, s),4.29 (2H, q, J=7.2 Hz), 7.24-7.30 (1H, m), 7.35-7.43 (4H, m), 8.13 (1H,brs).

Reference Example 76 Ethyl2-methyl-5-(3-thienyl)-1H-pyrrole-3-carboxylate

Using ethyl 2-acetyl-3-methyl-4-oxo-4-(3-thienyl)butanoate (1.86 g) andammonium acetate (626 mg), a procedure as in Reference Example 14 wasperformed to give the title compound as a brown oil (yield 1.57 g, 91%).

¹H-NMR (CDCl₃) δ: 1.36 (3H, t, J=7.2 Hz), 2.57 (3H, s), 4.29 (2H, q,J=7.2 Hz), 6.69-6.70 (1H, m), 7.17-7.18 (1H, m), 7.22-7.24 (1H, m),7.33-7.36 (1H, m), 8.38 (1H, brs).

Reference Example 77 Ethyl5-(4-fluorophenyl)-2-methyl-1H-pyrrole-3-carboxylate

4′-Fluoroacetophenone (13.8 g) was dissolved in chloroform (60 mL) anddiethyl ether (60 mL), and a solution of bromine (16.0 g) in chloroform(10 mL) was added dropwise while maintaining the reaction temperature atnot higher than 25° C. After completion of the dropwise addition, thereaction mixture was stirred at room temperature for 30 min, andextracted with ethyl acetate. The extract was washed with water anddried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure to give crude 2-bromo-1-(4-fluorophenyl)ethanone(23.2 g) as crystals. A solution (20 mL) of ethyl 3-oxobutanoate (11.7g) in N,N-dimethylformamide was added dropwise to a suspension (50 mL)of sodium hydride (60% in oil, 4.00 g) in N,N-dimethylformamide withstirring under ice-cooling. After stirring at the same temperature for15 min, a solution (10 mL) of crude 2-bromo-1-(4-fluorophenyl)ethanone(23.2 g) obtained above in N,N-dimethylformamide was added dropwise. Thereaction mixture was stirred at room temperature for 2 hr, water wasadded, and the mixture was extracted with diethyl ether. The extract waswashed with saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure to give crude ethyl2-acetyl-4-(4-fluorophenyl)-4-oxobutanoate as an oil (yield 23.20 g).Without further purification, the product was stirred with ammoniumacetate (11.56 g, 0.15 mol) and acetic acid (100 mL) with heating at 80°C. for 20 hr. The reaction mixture was concentrated under reducedpressure, dissolved in ethyl acetate, washed with water, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=7:2). The residue wascrystallized from hexane to give the title compound as crystals (yield13.6 g, from ethyl 3-oxobutanoate, 61%).

¹H-NMR (CDCl₃) δ: 1.36 (3H, t, J=7.1 Hz), 2.58 (3H, s), 4.29 (2H, q,J=7.1 Hz), 6.76 (1H, s), 7.06 (2H, t, J=8.7 Hz), 7.41 (2H, dd, J=8.9,5.1 Hz), 8.39 (1H, s).

Reference Example 78 Ethyl2-chloro-5-(pyridin-2-yl)-1H-pyrrole-3-carboxylate hydrochloride

2-Bromo-1-(pyridin-2-yl)ethanone hydrobromide (20 g) and potassiumcarbonate (14.8 g) were suspended in acetone (100 mL), and the mixturewas stirred at room temperature for 1.5 hr. Ethyl cyanoacetate (60.4 g)was dissolved in acetone (100 mL), potassium carbonate (29.6 g) wasadded and the mixture was stirred at 45° C. for 1 hr. The suspensionobtained earlier was added dropwise by small portions at the sametemperature. The reaction mixture was stirred at 45° C. for 3 hr, andthe insoluble material was filtered off. The filtrate was concentratedunder reduced pressure. The residue was suspended in ethyl acetate,washed with water and saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. A 4 mol/L hydrogenchloride-ethyl acetate solution (250 mL) was added to the obtained oiland the mixture was stirred at 60° C. for 3 hr and concentrated underreduced pressure. A saturated aqueous sodium hydrogencarbonate solutionwas added and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (eluent: hexane-ethyl acetate=4:1). A 4mol/L hydrogen chloride-ethyl acetate solution (20 mL) was added and themixture was concentrated under reduced pressure and crystallized fromethyl acetate to give the title compound as colorless crystals (yield3.08 g, 15%).

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=7.0 Hz), 4.25 (2H, q, J=7.0 Hz),7.48-7.54 (2H, m), 8.13-8.19 (2H, m), 8.61-8.63 (1H, m), 13.47 (1H, br).

Reference Example 79 Ethyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate

To a solution (80 mL) of ethyl2-chloro-5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate (8.6 g) in ethanolwas added 10% palladium carbon (50% containing water, 0.86 g), and themixture was stirred under a hydrogen atmosphere at room temperature for36 hr. The reaction mixture was filtrated, and the filtrate wasconcentrated under reduced pressure. The residue was dissolved inethanol (70 mL), 10% palladium carbon (50% containing water, 0.90 g) wasadded, and the mixture was stirred under a hydrogen atmosphere at roomtemperature for 60 hr. The reaction mixture was filtrated, and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=10:1→5:1) to give the title compound as a brown solid (yield1.37 g, 18%).

¹H-NMR (CDCl₃) δ: 1.67 (3H, t, J=7.2 Hz), 4.31 (2H, q, J=7.2 Hz),7.03-7.05 (1H, m), 7.08-7.25 (3H, m), 7.49-7.50 (1H, m), 7.58-30.7.66(1H, m), 9.22 (1H, brs).

Reference Example 80 Methyl5-(2-fluorophenyl)-4-methyl-1H-pyrrole-3-carboxylate

To a solution of methyl2-chloro-5-(2-fluorophenyl)-4-methyl-1H-pyrrole-3-carboxylate (10.2 g)in methanol (200 mL) was added 10% palladium carbon (50% containingwater, 1.28 g), and the mixture was stirred under a hydrogen atmosphereat room temperature for 20 hr. The reaction mixture was filtrated, andthe filtrate was concentrated under reduced pressure. A saturatedaqueous sodium hydrogencarbonate solution (100 mL) was added to theresidue, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated aqueous sodium hydrogencarbonate solution,water and saturated brine, dried over anhydrous sodium sulfate,filtrated, and concentrated under reduced pressure. The residue wasrecrystallized from ethyl acetate-hexane to give the title compound aswhite crystals (yield 6.70 g, 76%).

¹H-NMR (CDCl₃) δ: 2.40 (3H, s), 3.82 (3H, s), 7.12-7.33 (3H, m),7.42-7.49 (2H, m), 8.67 (1H, brs).

Reference Example 81 Ethyl 5-(pyridin-2-yl)-1H-pyrrole-3-carboxylate

Ethyl 2-chloro-5-(pyridin-2-yl)-1H-pyrrole-3-carboxylate hydrochloride(2.73 g) was dissolved in ethanol (200 mL), and 10% palladium carbon(50% containing water, 2.73 g) was added under a nitrogen atmosphere.Under a hydrogen atmosphere, the mixture was stirred at 50° C. for 15hr. The reaction mixture was filtrated, and the filtrate wasconcentrated under reduced pressure. Saturated aqueous sodiumhydrogencarbonate was added to the residue, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure to give the title compound as colorless crystals (yield1.73 g, 84%).

¹H-NMR (DMSO-d₆) δ: 1.28 (3H, t, J=7.2 Hz), 4.20 (2H, q, J=7.2 Hz),7.13-7.15 (1H, m), 7.19-7.23 (1H, m), 7.43-7.44 (1H, m), 7.75-7.83 (2H,m), 8.51-8.54 (1H, m), 12.11 (1H, brs).

Reference Example 82 Methyl 5-(2-methylphenyl)-1H-pyrrole-3-carboxylate

2′-Methylacetophenone (16.0 g) was dissolved in chloroform (50 mL) anddiethyl ether (50 mL), and a solution of bromine (16.0 g) in chloroform(15 mL) was added dropwise while maintaining the reaction temperature atnot higher than 25° C. After completion of the dropwise addition, thereaction mixture was stirred at room temperature for 30 min, andextracted with ethyl acetate. The extract was washed with water, driedover anhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure to give crude 2-bromo-1-(2-methylphenyl)ethanone (21.4g) as an oil. To a solution (700 mL) of methyl cyanoacetate (10.9 g) anddiisopropylethylamine (31.0 g) in tetrahydrofuran was added dropwise asolution (100 mL) of crude 2-bromo-1-(2-methylphenyl)ethanone (21.4 g)obtained above in tetrahydrofuran. The reaction mixture was stirred atroom temperature for 16 hr, then at 70° C. for 2 hr. The reactionmixture was filtrated, and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=4:1) to give methyl2-cyano-4-(2-methylphenyl)-4-oxobutanoate as an oil (yield 16.0 g). Thiswas dissolved in ethyl acetate (16 mL), 4 mol/L hydrogen chloride-ethylacetate solution (80 mL) was added, and the mixture was stirred at roomtemperature for 16 hr. The reaction mixture was concentrated underreduced pressure, water was added to the residue, and the mixture wasextracted with ethyl acetate. The extract was washed with water, 6%aqueous sodium hydrogencarbonate solution and saturated brine, driedover anhydrous sodium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1) to give methyl2-chloro-5-(2-methylphenyl)-1H-pyrrole-3-carboxylate as an oil (yield2.7 g). This was dissolved in methanol (15 mL), 10% palladium carbon(50% containing water, 1.0 g) was added, and the mixture was stirredunder a hydrogen atmosphere at room temperature for 18 hr. The reactionmixture was filtrated, and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=4:1) to give the title compound as acolorless solid (yield 0.66 g, 3%).

¹H-NMR (CDCl₃) δ: 2.44 (3H, s), 3.84 (3H, s), 6.72-6.73 (1H, m),7.22-7.34 (4H, m), 7.42-7.50 (1H, m), 8.50 (1H, brs).

Reference Example 83 Ethyl4-chloro-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate

To a solution (20 mL) of ethyl2-methyl-5-phenyl-1H-pyrrole-3-carboxylate (1.0 g) inN,N-dimethylformamide was added N-chlorosuccinimide (874 mg) at 0° C.The reaction mixture was stirred at room temperature for 4 hr, 6%aqueous sodium hydrogencarbonate solution was added, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=9:1→4:1) to give the titlecompound as colorless crystals (yield 509 mg, 44%).

¹H-NMR (CDCl₃) δ: 1.39 (3H, t, J=7.2 Hz), 2.56 (3H, s), 4.34 (2H, q,J=7.2 Hz), 7.28-7.34 (1H, m), 7.39-7.45 (2H, m), 7.59-7.63 (2H, m), 8.22(1H, br).

Reference Example 84 Ethyl 2-fluoro-5-phenyl-1H-pyrrole-3-carboxylate

To a solution (70 mL) of ethyl 5-phenyl-1H-pyrrole-3-carboxylate (1.0 g)in tetrahydrofuran was added xenone difluoride (944 mg) under a nitrogenatmosphere, and the mixture was stirred at room temperature for 72 hr.Water was added to the reaction mixture, and the mixture was extractedwith ethyl acetate. The extract was washed with saturated brine, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=9:1→4:1) to give the title compound aspale-red crystals (yield 350 mg, 32%).

¹H-NMR (CDCl₃) δ: 1.36 (3H, t, J=7.1 Hz), 4.32 (2H, q, J=7.1 Hz),6.66-6.68 (1H, m), 7.23-7.29 (1H, m), 7.35-7.45 (4H, m), 8.51 (1H, brs).

Reference Example 85 Ethyl2-chloro-4-fluoro-5-phenyl-1H-pyrrole-3-carboxylate

To a solution (100 mL) of ethyl2-chloro-5-phenyl-1H-pyrrole-3-carboxylate (2.0 g) in tetrahydrofuranwas added xenone difluoride (1.85 g) under a nitrogen atmosphere, andthe mixture was stirred at room temperature for 72 hr. The reactionmixture was concentrated under reduced pressure, and residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=9:1→4:1) to give the title compound as colorless crystals (yield350 mg, 15%).

¹H-NMR (CDCl₃) δ: 1.37-1.42 (3H, m), 4.33-4.41 (2H, m), 7.28-7.62 (5H,m).

Reference Example 86 Ethyl 4-fluoro-5-phenyl-1H-pyrrole-3-carboxylate

To a solution (30 mL) of ethyl2-chloro-4-fluoro-5-phenyl-1H-pyrrole-3-carboxylate (300 mg) in ethanolwas added 10% palladium carbon (50% water-containing product, 0.3 g),and the mixture was stirred under a hydrogen atmosphere at roomtemperature for 24 hr. The reaction mixture was filtrated, and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=4:1) to give the title compound as a colorless oil (yield 100mg, 38%).

¹H-NMR (CDCl₃) δ: 1.37 (3H, t, J=7.2 Hz), 4.34 (2H, q, J=7.2 Hz),7.22-7.54 (6H, m), 8.42 (1H, br).

Reference Example 87 Methyl (2E)-hex-2-enoate

To a solution (100 mL) of (2E)-hex-2-enoic acid (5.0 g) intetrahydrofuran were added dropwise under ice-cooling oxalyl chloride(3.76 mL) and N,N-dimethylformamide (1 mL). The mixture was stirred atthe same temperature for 30 min, methanol (10 mL) was gradually added tothe reaction mixture, and the mixture was stirred at room temperaturefor 2 hr. The solvent was evaporated under reduced pressure, and theresidue was treated with 6% aqueous sodium hydrogencarbonate solution,and extracted with diethyl ether. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure (50 Torr, water bath 10° C.) to give the title compoundas a colorless oil (yield 5.67 g, about 100%).

¹H-NMR (CDCl₃) δ: 0.94 (3H, t, J=7.5 Hz), 1.43-1.53 (2H, m), 2.14-2.21(2H, m), 3.73 (3H, s), 5.82 (1H, dt, J=1.8, 15.6 Hz), 6.97 (1H, dt,J=6.9, 15.6 Hz).

Reference Example 88 Methyl 4-methyl-1H-pyrrole-3-carboxylate

Using p-toluenesulfonylmethyl isocyanide (94.6 g), methyl crotonate(48.5 g) and potassium tert-butoxide (76.7 g), a procedure as inReference Example 39 was performed to give the title compound as apale-yellow solid (yield 16.8 g, 25%).

¹H-NMR (CDCl₃) δ: 2.29 (3H, s), 3.80 (3H, s), 6.53-6.54 (1H, m),7.36-7.38 (1H, m), 8.25 (1H, brs).

Reference Example 89 Methyl 4-ethyl-1H-pyrrole-3-carboxylate

Using p-toluenesulfonylmethyl isocyanide (10.1 g), methyl 2-pentenoate(6.01 g) and potassium tert-butoxide (7.01 g), a procedure as inReference Example 39 was performed to give the title compound aspale-yellow crystals (yield 5.05 g, 64%).

¹H-NMR (CDCl₃) δ: 1.21 (3H, t, J=7.5 Hz), 2.73-2.81 (2H, m), 3.80 (3H,s), 6.55-6.56 (1H, m), 7.37-7.39 (1H, m), 8.36 (1H, brs).

Reference Example 90 Methyl 4-propyl-1H-pyrrole-3-carboxylate

Using p-toluenesulfonylmethyl isocyanide (8.6 g), methyl(2E)-hex-2-enoate (5.67 g) and potassium tert-butoxide (5.9 g), aprocedure as in Reference Example 39 was performed to give the titlecompound as colorless crystals (yield 2.8 g, 38%).

¹H-NMR (CDCl₃) δ: 0.96 (3H, t, J=7.5 Hz), 1.57-1.66 (2H, m), 2.68-2.73(2H, m), 3.79 (3H, m), 6.53-6.55 (1H, m), 7.36-7.38 (1H, m), 8.40 (1H,br).

Reference Example 91 Methyl 4-isopropyl-1H-pyrrole-3-carboxylate

Using p-toluenesulfonylmethyl isocyanide (7.6 g), methyl(2E)-4-methylpent-2-enoate (5.0 g) and potassium tert-butoxide (5.25 g),a procedure as in Reference Example 39 was performed to give the titlecompound as a pale-yellow oil (yield 3.5 g, 54%).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 3.35-3.45 (1H, m), 3.79 (3H,s), 6.55-6.57 (1H, m), 7.36-7.38 (1H, m), 8.30 (1H, br).

Reference Example 92 Methyl 4-phenyl-1H-pyrrole-3-carboxylate

Using p-toluenesulfonylmethyl isocyanide (10.1 g), methyl cinnamate(8.33 g) and potassium tert-butoxide (6.97 g), a procedure as inReference Example 39 was performed to give the title compound aspale-yellow crystals (yield 5.40 g, 52%).

¹H-NMR (CDCl₃) δ: 3.74 (3H, s), 6.77-6.79 (1H, m), 7.25-7.38 (3H, m),7.47-7.51 (3H, m), 8.54 (1H, brs).

Reference Example 93 1-[(1-Isocyanopentyl)sulfonyl]-4-methylbenzene

A mixture of p-toluenesulfonylmethyl isocyanide (9.75 g),tetrabutylammonium iodide (3.69 g), 1-butyl iodide (11.3 mL),dichloromethane (100 mL) and 30% aqueous sodium hydroxide solution (100mL) was stirred at room temperature for 12 hr. The reaction product wasdiluted with water (200 mL), and extracted with dichloromethane. Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The obtained gum-likeresidue was extracted 3 times with diethyl ether (100 mL). The extractwas concentrated under reduced pressure to give the title compound as acolorless oil (yield 10.8 g, 86%).

¹H-NMR (CDCl₃) δ: 0.92-0.97 (3H, m), 1.40-1.60 (4H, m), 1.80-1.90 (1H,m), 2.10-2.25 (1H, m), 2.49 (3H, s), 4.41-4.48 (1H, m), 7.41-7.51 (2H,m), 7.85-7.89 (2H, m).

Reference Example 94 Ethyl 5-butyl-1H-pyrrole-3-carboxylate

A solution (120 mL) of 1-[(1-isocyanopentyl)sulfonyl]-4-methylbenzene(10.8 g) and ethyl acrylate (4.78 mL) in tetrahydrofuran was addeddropwise to a solution (80 mL) of potassium tert-butoxide (5.79 g) intetrahydrofuran while stirring at room temperature over 1 hr. Themixture was further stirred at the same temperature for 30 min, and thereaction product was diluted with water, and extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→8:2) to give the title compound as a yellowoil (yield 6.56 g, 78%).

¹H-NMR (CDCl₃) δ: 0.89-0.95 (3H, m), 1.24-1.45 (5H, m), 1.55-1.65 (2H,m), 2.55-2.60 (2H, m), 4.23-4.30 (2H, m), 6.33 (1H, s), 7.30 (1H, s),8.11 (1H, br).

Reference Example 95 Ethyl 5-cyclohexyl-1H-pyrrole-3-carboxylate

Under an argon atmosphere, to a solution of ethyl1H-pyrrole-3-carboxylate (2.09 g) and aluminum(III) chloride (4.0 g) incarbon disulfide (30 mL) was added bromocyclohexane (1.84 mL) underice-cooling with stirring, and the mixture was stirred at roomtemperature for 30 min. The mixture was heated to 50° C., and stirredfor 2 hr. The reaction product was cooled to room temperature, pouredinto ice water, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=19:1→8:2), and recrystallized from hexane to give the titlecompound as a colorless solid (yield 530 mg, 16%).

¹H-NMR (CDCl₃) δ: 1.20-1.99 (13H, m), 2.52 (1H, m), 4.23-4.30 (2H, m),6.33 (1H, s), 7.30 (1H, s), 8.15 (1H, br).

Reference Example 96 Ethyl 2-methyl-1H-pyrrole-3-carboxylate

Vinyl acetate (13.4 g) was added dropwise over 2 hr to bromine (25 g)with stirring under ice-cooling. The reaction mixture was furtherstirred at the same temperature for 1 hr. Ethyl 3-oxobutanoate (18.5 g)was added, and 25% aqueous ammonia solution (44 mL) was added dropwiseover 1 hr. The reaction mixture was further stirred at room temperaturefor 30 min, water was added and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→3:1) and recrystallized from hexane to givethe title compound as a colorless solid (yield 7.56 g, 35%).

¹H-NMR (CDCl₃) δ: 1.32-1.37 (3H, m), 2.53 (3H, s), 4.24-4.31 (2H, m),6.55-6.58 (2H, m), 8.13 (1H, br).

Reference Example 97 Methyl 5-bromo-4-methyl-1H-pyrrole-3-carboxylate

By a similar operation as in Reference Example 40 and using methyl4-methyl-1H-pyrrole-3-carboxylate (1.0 g) and N-bromosuccinimide (1.28g), the title compound was obtained as a pale-yellow solid (yield 489mg, 31%).

¹H-NMR (CDCl₃) δ: 2.23 (3H, s), 3.80 (3H, s), 7.37 (1H, d, J=3.0 Hz),8.40 (1H, brs).

Reference Example 98 Methyl 5-bromo-4-ethyl-1H-pyrrole-3-carboxylate

Using methyl 4-ethyl-1H-pyrrole-3-carboxylate (2.32 g) andN-bromosuccinimide (2.74 g), a procedure as in Reference Example 40 wasperformed to give the title compound as white crystals (yield 2.96 g,84%).

¹H-NMR (CDCl₃) δ: 1.13 (3H, t, J=4.5 Hz), 2.70 (2H, q, J=4.5 Hz), 3.81(3H, s), 7.37 (1H, d, J=3.0 Hz), 8.30 (1H, brs).

Reference Example 99 Methyl 5-bromo-4-propyl-1H-pyrrole-3-carboxylate

Using methyl 4-propyl-1H-pyrrole-3-carboxylate (2.8 g),N-bromosuccinimide (3.0 g) and pyridine (0.5 mL), a procedure as inReference Example 40 was performed to give the title compound ascolorless crystals (yield 2.96 g, 72%).

¹H-NMR (CDCl₃) δ: 0.93 (3H, t, J=7.5 Hz), 1.50-1.60 (2H, m), 2.62-2.68(2H, m), 3.80 (3H, s), 7.38 (1H, d, J=3.0 Hz), 8.41 (1H, br).

Reference Example 100 Methyl5-bromo-4-isopropyl-1H-pyrrole-3-carboxylate

Using methyl 4-isopropyl-1H-pyrrole-3-carboxylate (3.5 g),N-bromosuccinimide (3.74 g) and pyridine (0.5 mL), a procedure as inReference Example 40 was performed to give the title compound ascolorless crystals (yield 3.29 g, 64%).

¹H-NMR (CDCl₃) δ: 1.32 (6H, d, J=7.2 Hz), 3.45-3.55 (1H, m), 3.79 (3H,s), 7.36 (1H, d, J=3.3 Hz), 8.27 (1H, br).

Reference Example 101 Methyl 5-bromo-4-phenyl-1H-pyrrole-3-carboxylate

Using methyl 4-phenyl-1H-pyrrole-3-carboxylate (2.01 g) andN-bromosuccinimide (1.85 g), a procedure as in Reference Example 40 wasperformed to give the title compound as white crystals (yield 1.97 g,70%).

¹H-NMR (CDCl₃) δ: 3.69 (3H, s), 7.30-7.43 (5H, m), 7.48 (1H, d, J=3.0Hz), 8.54 (1H, brs).

Reference Example 102 Ethyl 5-bromo-2-methyl-1H-pyrrole-3-carboxylate

To a solution of ethyl 2-methyl-1H-pyrrole-3-carboxylate (1.53 g) intetrahydrofuran (20 mL) was added N-bromosuccinimide (1.78 g) at −78°C., and the mixture was stirred at the same temperature for 30 min.Water was added to the reaction mixture, and the mixture was extractedwith diethyl ether. The extract was washed with saturated brine, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure at not more than 5° C. The residue washed with hexane to givethe title compound as a colorless solid (yield 2.26 g, 97%).

¹H-NMR (CDCl₃) δ: 1.30-1.35 (3H, m), 2.51 (3H, s), 4.22-4.29 (2H, m),6.50 (1H, s), 8.01 (1H, br).

Reference Example 103 Methyl5-bromo-1-(phenylsulfonyl)-4-propyl-1H-pyrrole-3-carboxylate

Using methyl 5-bromo-4-propyl-1H-pyrrole-3-carboxylate (2.96 g), sodiumhydride (60% in oil, 634 mg) and benzenesulfonyl chloride (2.33 g), aprocedure as in Reference Example 41 was performed to give the titlecompound as colorless crystals (yield 3.96 g, 85%).

¹H-NMR (CDCl₃) δ: 0.87 (3H, t, J=7.5 Hz), 1.43-1.60 (2H, m), 2.54-2.60(2H, m), 3.83 (3H, s), 7.53-7.59 (2H, m), 7.65-7.71 (1H, m), 7.93-7.97(2H, m), 8.11 (1H, s).

Reference Example 104 Methyl5-bromo-4-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate

Using sodium hydride (60% in oil, 281 mg), ethyl5-bromo-4-phenyl-1H-pyrrole-3-carboxylate (1.70 g) and benzenesulfonylchloride (0.9 mL), a procedure as in Reference Example 41 was performedto give the title compound as white crystals (yield 2.51 g, 93%).

¹H-NMR (CDCl₃) δ: 3.71 (3H, s), 7.23-7.26 (3H, m), 7.31-7.40 (3H, m),7.57-7.62 (2H, m), 7.68-7.74 (1H, m), 8.01-8.05 (2H, m), 8.24 (1H, s).

Reference Example 105 Methyl 5-phenyl-4-propyl-1H-pyrrole-3-carboxylate

Using methyl5-bromo-1-(phenylsulfonyl)-4-propyl-1H-pyrrole-3-carboxylate (3.96 g),phenylboronic acid (2.5 g), tetrakis(triphenylphosphine)palladium (1.79g) and sodium carbonate (3.28 g), a procedure as in Reference Example 56was performed to give the title compound as a pale-yellow oil (yield 2.0g, 80%).

¹H-NMR (CDCl₃) δ: 0.95 (3H, t, J=7.5 Hz), 1.60-1.68 (2H, m), 2.76-2.81(2H, m), 3.82 (3H, s), 7.31-7.46 (6H, m), 8.37 (1H, br).

Reference Example 106 Methyl 4,5-diphenyl-1H-pyrrole-3-carboxylate

Using methyl5-bromo-4-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (1.01 g),phenylboronic acid (439 mg), sodium carbonate (771 mg) andtetrakis(triphenylphosphine)palladium (420 mg), a procedure as inReference Example 56 was performed to give the title compound aspale-yellow crystals (yield 506 mg, 76%).

¹H-NMR (CDCl₃) δ: 3.69 (3H, s), 7.12-7.32 (10H, m), 7.55 (1H, d, J=3.3Hz), 8.54 (1H, brs).

Reference Example 107[5-(2-Fluorophenyl)-4-methyl-1H-pyrrol-3-yl]methanol

By a similar operation as in Reference Example 64 and using methyl5-(2-fluorophenyl)-4-methyl-1H-pyrrole-3-carboxylate (1.63 g) and a 1.5mol/L solution (15 mL) of diisobutylaluminum hydride in toluene, thetitle compound was obtained as white crystals (yield 1.18 g, 82%).

¹H-NMR (CDCl₃) δ: 1.30 (1H, t, J=4.8 Hz), 2.25 (3H, s), 4.61 (2H, d,J=4.8 Hz), 6.87 (1H, d, J=3.3 Hz), 7.10-7.28 (3H, m), 7.44-7.50 (1H, m),8.40 (1H, brs).

Reference Example 108 [(5-Pyridin-2-yl)-1H-pyrrol-3-yl]methanol

A solution (30 mL) of ethyl 5-(pyridin-2-yl)-1H-pyrrole-3-carboxylate(1.62 g) in tetrahydrofuran was cooled to −50° C., and a 1.5 mol/Lsolution (15 mL) of diisobutylaluminum hydride in toluene was addeddropwise by small portions. The mixture was further stirred at 0° C. for1 hr, water (3 mL) was added to the reaction mixture and the mixture wasstirred at room temperature for 1 hr. Celite and anhydrous magnesiumsulfate were added and the mixture was further stirred for 15 min andfiltrated. The obtained filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=1:1→1:3) to give the title compound ascolorless crystals (yield 1.15 g, 88%).

¹H-NMR (CDCl₃) δ: 4.61 (2H, s), 6.73-6.74 (1H, m), 6.88-6.89 (1H, m),7.02-7.07 (1H, m), 7.50-7.54 (1H, m), 7.61-7.66 (1H, m), 8.43-8.45 (1H,m), 9.71 (1H, br).

Reference Example 1095-(2-Fluorophenyl)-4-methyl-1H-pyrrole-3-carbaldehyde

Using [5-(2-fluorophenyl)-4-methyl-1H-pyrrol-3-yl]methanol (1.17 g),tetra-n-propylammonium perruthenate (101 mg), N-methylmorpholine N-oxide(1.01 g) and molecular sieves 4A powder (572 mg), a procedure as inReference Example 65 was performed to give the title compound aspale-pink crystals (yield 0.67 g, 58%).

¹H-NMR (CDCl₃) δ: 2.45 (3H, s), 7.14-7.36 (3H, m), 7.44-7.50 (2H, m),8.82 (1H, brs), 9.92 (1H, s).

Reference Example 110 5-(Pyridin-2-yl)-1H-pyrrole-3-carbaldehyde

To a solution (50 mL) of [(5-pyridin-2-yl)-1H-pyrrol-3-yl]methanol (0.96g) in acetonitrile were added tetra-n-propylammonium perruthenate (194mg), N-methylmorpholine N-oxide (2.98 g) and molecular sieves 4A powder(5 g), and the mixture was stirred at room temperature for 3 hr. Thereaction mixture was diluted with ethyl acetate, filtered throughcelite, and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1→1:1) to give the title compound as colorlesscrystals (yield 270 mg, 29%).

¹H-NMR (CDCl₃) δ: 7.14-7.18 (2H, m), 7.52 (1H, br), 7.61-7.64 (1H, m),7.69-7.74 (1H, m), 8.49-8.51 (1H, m), 9.85 (1H, s), 10.28 (1H, br).

Reference Example 111 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde

A solution (220 mL) of ethyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate(11.6 g) in tetrahydrofuran was cooled to −78° C., and a 1.5 mol/Lsolution (100 mL) of diisobutylaluminum hydride in toluene was addeddropwise over 10 min. The mixture was stirred at −78° C. for 1 hr andwater (10 mL) was added dropwise over 2 min. The mixture was allowed towarm to room temperature and stirred for 2 hr. To the reaction mixturewere added celite and anhydrous magnesium sulfate and the mixture wasfiltered. The filtrate was concentrated under reduced pressure to give apale-yellow oil (yield 8.30 g). To a solution (220 mL) of the obtainedpale-yellow oil (8.30 g) in acetonitrile were addedtetra-n-propylammonium perruthenate (1.75 g), N-methylmorpholine N-oxide(13.5 g) and molecular sieves 4A powder (5 g), and the mixture wasstirred at room temperature for 1.5 hr. The reaction mixture wasfiltered through celite, and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=7:3→1:1) to give the title compound asyellow crystals (yield 5.6 g, 60%).

¹H-NMR (CDCl₃) δ: 7.07-7.28 (4H, m), 7.52-7.54 (1H, m), 7.61-7.67 (1H,m), 9.49 (1H, brs), 9.86 (1H, s).

Reference Example 1125-[2-(Trifluoromethyl)phenyl]-1H-pyrrole-3-carbaldehyde

A solution (28 mL) of ethyl5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate (1.38 g) intetrahydrofuran was cooled to −78° C., and a 1.5 mol/L solution (13 mL)of diisobutylaluminum hydride in toluene was added dropwise over 10 min.The mixture was further stirred at −78° C. for 1 hr, and water (3 mL)was added dropwise over 2 min. The mixture was allowed to warm to roomtemperature and further stirred for 1 hr. To the reaction mixture wereadded celite and anhydrous magnesium sulfate, and the mixture wasfiltered. The filtrate was concentrated under reduced pressure to give apale-yellow oil (yield 1.14 g). The obtained oil (1.14 g) was dissolvedin acetonitrile (50 mL), and tetra-n-propylammonium perruthenate (0.26g), N-methylmorpholine N-oxide (1.32 g) and molecular sieves 4A powder(5 g) were added to this solution. The mixture was stirred at roomtemperature for 1.5 hr. The reaction mixture was filtered throughcelite, and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1→1:1) to give the title compound as colorlesscrystals (yield 0.71 g, 61%).

¹H-NMR (CDCl₃) δ: 6.79-6.81 (1H, m), 7.46-7.78 (5H, m), 9.13 (1H, br),9.822 (1H, s).

Reference Example 113 5-(2-Methylphenyl)-1H-pyrrole-3-carbaldehyde

Using ethyl 5-(2-methylphenyl)-1H-pyrrole-3-carboxylate (659 mg), aprocedure as in Reference Example 111 was performed to give the titlecompound as yellow crystals (yield 309 mg, 55%)

¹H-NMR (CDCl₃) δ: 2.44 (3H, s), 6.75-6.76 (1H, m), 7.24-7.35 (4H, m),7.49-7.51 (1H, m), 8.80 (H, brs), 9.84 (1H, s).

Reference Example 114 4-Amino-2-fluorobenzonitrile

To a solution of 2-fluoro-4-nitrobenzonitrile (2.51 g) in methanol (125mL) was added 10% palladium carbon (50% containing water, 237 mg), andthe mixture was stirred under a hydrogen atmosphere for 3 hr. Thereaction mixture was filtrated, and the filtrate was concentrated underreduced pressure. The residue was purified by basic silica gel columnchromatography (eluent: hexane-ethyl acetate=1:1) to give the titlecompound as a pale-yellow solid (yield 1.43 g, 70%).

¹H-NMR (CDCl₃) δ: 4.31 (2H, brs), 6.37-6.45 (2H, m), 7.31-7.36 (1H, m).

Reference Example 115 (4-Cyano-3-fluorobenzene)sulfonyl chloride

To a mixture of 4-amino-2-fluorobenzonitrile (433 mg) and concentratedhydrochloric acid (4 mL) was slowly added an aqueous solution (2 mL) ofsodium nitrite (658 mg) at 0° C. and the mixture was stirred at the sametemperature for 15 min. Concentrated hydrochloric acid (2 mL) and copper(II) sulfate (53.1 mg) were added to the reaction mixture, then asolution of sodium bisulfite (3.58 g) in water (6 mL) was added at 0°C., and the mixture was stirred at the same temperature for 30 min.Water (50 mL) was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The extract was washed with water andsaturated brine, dried over anhydrous magnesium sulfate, and filtrated.The filtrate was concentrated under reduced pressure to give the titlecompound as a white solid (yield 713 mg, about 100%).

¹H-NMR (CDCl₃) δ: 7.91-8.00 (3H, m).

Reference Example 116 (3-Chloro-4-cyanobenzene)sulfonyl chloride

Using 4-amino-2-fluorobenzonitrile (461 mg), sodium nitrite (626 mg),copper (II) sulfate (54.6 mg) and sodium bisulfite (3.41 g), a procedureas in Reference Example 115 was performed to give the title compound asa white solid (yield 679 mg, 95%).

¹H-NMR (CDCl₃) δ: 7.96 (1H, d, J=8.1 Hz), 8.06 (1H, dd, J=8.1, 2.1 Hz),8.19 (1H, t, J=2.1 Hz).

Reference Example 117 1-Benzothiophene 1,1-dioxide

To a solution (120 mL) of 1-benzothiophene (11.2 g) in tetrahydrofuranwas added m-chloroperbenzoic acid (70% containing, 43.1 g) at 0° C. andthe mixture was stirred at the same temperature for 1 hr, furtherstirred at room temperature for 1 hr. An aqueous sodium thiosulfatesolution (50 mL) was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The extract was washed with 1 mol/Laqueous sodium hydroxide solution, saturated aqueous sodiumhydrogencarbonate solution, water and saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was recrystallized from ethyl acetate to give the titlecompound as a white solid (yield 10.3 g, 74%).

¹H-NMR (CDCl₃) δ: 6.72 (1H, d, J=7.0 Hz), 7.20-7.24 (1H, m), 7.34-7.38(1H, m), 7.52-7.60 (2H, m), 7.70-7.74 (1H, m).

Reference Example 118 6-Nitro-1-benzothiophene 1,1-dioxide

Nitric acid (10 mL) was slowly added to sulfuric acid (10 mL) at 0° C.,and the mixture was stirred at the same temperature for 10 min. To thissolution was slowly added 1-benzothiophene 1,1-dioxide (3.99 g) at 0°C., and the mixture was further stirred at the same temperature for 30min. The reaction mixture was poured into ice water, and the mixture wasextracted with ethyl acetate. The extract was washed twice with water,saturated aqueous sodium hydrogencarbonate solution and saturated brine,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was recrystallized from ethyl acetate-hexane togive the title compound as a pale-yellow solid (yield 4.26 g, 84%).

¹H-NMR (CDCl₃) δ: 7.00 (1H, d, J=6.9 Hz), 7.33 (1H, dd, J=1.2, 6.9 Hz),7.58 (1H, d, J=8.4 Hz), 8.47 (1H, dd, J=1.8, 8.4 Hz), 8.55-8.57 (1H, m).

Reference Example 119 2,3-Dihydro-1-benzothiophene-6-amine 1,1-dioxide

To a suspension of 6-nitro-1-benzothiophene 1,1-dioxide (2.02 g) inethanol (200 mL) and methanol (60 mL) was added 10% palladium carbon(50% containing water, 265 mg), and the mixture was stirred under ahydrogen atmosphere for 12 hr. The reaction mixture was filtrated, andthe filtrate was concentrated under reduced pressure. The residue wasrecrystallized from ethyl acetate to give the title compound as a whitesolid (yield 1.31 g, 75%).

¹H-NMR (CDCl₃) δ: 3.25 (2H, t, J=6.9 Hz), 3.44-3.49 (2H, m), 3.93 (2H,brs), 6.84-6.87 (1H, m), 6.94-6.95 (1H, m), 7.12 (1H, d, J=8.1 Hz).

Reference Example 120 6-(2,3-Dihydro-1-benzothiophene)sulfonyl chloride1,1-dioxide

Using 2,3-dihydro-1-benzothiophene-6-amine 1,1-dioxide (1.06 g), sodiumnitrite (1.21 g), copper (II) sulfate (96.9 mg) and sodium bisulfite(6.48 g), a procedure as in Reference Example 115 was performed to givethe title compound as a white solid (yield 0.92 g, 60%).

¹H-NMR (CDCl₃) δ: 3.51-3.56 (2H, m), 3.60-3.65 (2H, m), 7.66-7.69 (1H,m), 8.22-8.26 (1H, m), 8.41-8.42 (1H, m).

Reference Example 121 1,3-Benzothiazol-6-ylsulfonyl chloride

Using 6-aminobenzothiazole (1.55 g), sodium nitrite (2.19 g), copper(II) sulfate (173 mg) and sodium bisulfite (10.2 g), a procedure as inReference Example 115 was performed to give the title compound as awhite solid (yield 0.30 g, 12%).

¹H-NMR (CDCl₃) δ: 8.17-8.21 (1H, m), 8.35-8.38 (1H, m), 8.73-8.74 (1H,m), 9.33 (1H, s).

Reference Example 122 Methyl 3-(chlorosulfonyl)benzoate

A solution (20 mL) of 3-(chlorosulfonyl)benzoyl chloride (2.4 g) indichloromethane was cooled to 0° C., and pyridine (791 mg) and methanol(320 mg) were added. The reaction mixture was stirred at roomtemperature for 2 hr, and the solvent was evaporated under reducedpressure. The residue was filtrated, washed with a mixed solvent ofethyl acetate and isopropyl ether, and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=9:1→4:1) to give the titlecompound as a colorless oil (yield 2.17 g, 92%).

¹H-NMR (CDCl₃) δ: 3.99 (3H, s), 7.74 (1H, t, J=8.1 Hz), 8.21-8.24 (1H,m), 8.39-8.43 (1H, m), 8.69-8.70 (1H, m).

Reference Example 123 3-(Ethylthio)aniline

Sodium hydride (60% in oil, 2.3 g) was suspended in a mixed solvent oftetrahydrofuran (35 mL) and N,N-dimethylformamide (15 mL), and3-aminobenzenethiol (5.0 g) was added dropwise at room temperature. Themixture was stirred at the same temperature for 5 min, iodoethane (6.86g) was added, and the mixture was stirred for 30 min. Water was added tothe reaction mixture, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=9:1→4:1) to give the title compound as a yellow oil (yield 5.0g, 82%).

¹H-NMR (CDCl₃) δ: 1.31 (3H, t, J=7.5 Hz), 2.92 (2H, q, J=7.5 Hz), 3.69(2H, br), 6.47-6.51 (1H, m), 6.65-6.66 (1H, m), 6.70-6.73 (1H, m),7.04-7.09 (1H, m).

Reference Example 124 3-(Ethylsulfonyl)aniline

To a solution (75 mL) of 3-(ethylthio)aniline (5.0 g) in methanol wasadded dropwise an aqueous solution (150 mL) of OXONE® (30 g) at 0° C.The mixture was stirred at room temperature for 2 hr, and methanol wasevaporated under reduced pressure. The residue was basified withsaturated aqueous sodium hydrogencarbonate solution, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=9:1→4:1) to give the titlecompound as a yellow oil (yield 4.6 g, 77%).

¹H-NMR (CDCl₃) δ: 1.28 (3H, t, J=7.5 Hz), 3.10 (2H, q, J=7.5 Hz), 3.95(2H, br), 6.88-6.92 (1H, m), 7.16-7.18 (1H, m), 7.22-7.35 (2H, m).

Reference Example 125 3-(Ethylsulfonyl)benzenesulfonyl chloride

Using 3-(ethylsulfonyl)aniline (1.0 g), a procedure as in ReferenceExample 115 was performed to give the title compound as a colorless oil(yield 594 mg, 41%).

¹H-NMR (CDCl₃) δ: 1.35 (3H, t, J=7.5 Hz), 3.21 (2H, q, J=7.5 Hz),7.87-7.92 (1H, m), 8.27-8.35 (2H, m), 8.57-8.58 (1H, m).

Reference Example 126 4-[(Trifluoromethyl)sulfonyl]benzenesulfonylchloride

Under ice-cooling, thionyl chloride (2.7 mL) was added dropwise to water(16 mL) over 30 min. The mixture was stirred at room temperature for 12hr to give a sulfur dioxide-containing solution. Under ice-cooling,{4-[(trifluoromethyl)sulfonyl]phenyl}amine (2.0 g) was added toconcentrated hydrochloric acid (9 mL) and the mixture was stirred. Anaqueous solution (3 mL) of sodium nitrite (0.67 g) was added dropwisewhile maintaining the inside temperature at not higher than 5° C. andthe mixture was further stirred for 15 min. The mixture was graduallyadded at 5° C. to a mixture of the above-mentioned sulfurdioxide-containing solution added with cuprous chloride (10 mg). Underice-cooling, the mixture was further stirred for 30 min. After stirring,the precipitated product was collected by filtration, washed with water,and dried in the presence of phosphorus pentoxide under reduced pressureat 50° C. to give the title compound (yield 2.3 g, 84%).

¹H-NMR (CDCl₃) δ: 8.35 (4H, s).

Reference Example 127 3-[(Trifluoromethyl)sulfonyl]benzenesulfonylchloride

Under ice-cooling, thionyl chloride (4 mL) was added dropwise to water(24 mL) over 30 min. The mixture was stirred at room temperature for 12hr to give a sulfur dioxide-containing solution. Under ice-cooling,{3-[(trifluoromethyl)sulfonyl]phenyl}amine (1.0 g) was added toconcentrated hydrochloric acid (6 mL) and the mixture was stirred. Anaqueous solution (2 mL) of sodium nitrite (0.34 g) was added dropwisewhile maintaining the inside temperature at not higher than 5° C. andthe mixture was further stirred for 15 min. The mixture was graduallyadded at 5° C. to a mixture of the above-mentioned sulfurdioxide-containing solution added with cuprous chloride (10 mg). Underice-cooling, the mixture was further stirred for 30 min, and extractedwith ethyl acetate. The extract was dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=9:1→7:3) to give the title compound as a pale-yellow oil (yield1.08 g, 79%).

¹H-NMR (CDCl₃) δ: 8.02 (1H, t, J=8.1 Hz), 8.40 (1H, d, J=7.8 Hz), 8.50(1H, d, J=8.1 Hz), 8.69 (1H, s).

Reference Example 128 2-Hydroxy-5-pyrimidinesulfonic acid

Fuming sulfuric acid (containing 25% sulfur dioxide, 100 mL) was cooledto 0° C., and 2-aminopyrimidine (25 g) was gradually added over 1 hr.The mixture was heated to 180° C. and stirred for 40 hr. After coolingto room temperature, the mixture was poured into ice (1 kg). Theprecipitate was collected by filtration and recrystallized from water togive the title compound (yield 25.6 g, 55%).

¹H-NMR (DMSO-d₆) δ: 6.20-7.20 (2H, m), 8.71 (2H, s).

Reference Example 129 2-Chloro-5-pyrimidinesulfonyl chloride

A mixture of 2-hydroxy-5-pyrimidinesulfonic acid (12.8 g) and phosphoruspentachloride (37.8 g) was stirred under reflux at 180° C. for 4 hr.After cooling to room temperature, toluene (200 mL) was added, and theinsoluble material was filtered off. The filtrate was washed with icewater, dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was stood in a freezerfor one day to give the title compound as a pale-yellow solid (yield14.8 g, 96%).

¹H-NMR (CDCl₃) δ: 9.19 (2H, s).

Reference Example 130 6-Chloropyridazine-3-thiol

To a suspension (88 mL) of sodium hydrogensulfide (3.78 g) in ethanolwas added 3,6-dichloropyridazine (5.0 g), and the mixture was heatedunder refluxed for 1 hr. The solvent was evaporated under reducedpressure, and water (12.5 mL) was added. The mixture was adjusted toabout pH 9 with 2 mol/L aqueous sodium hydroxide solution, and theprecipitate was filtered off. The filtrate was adjusted to about pH 2with 6 mol/L hydrochloric acid and the precipitate was collected byfiltration to give the title compound as a yellow solid (yield 4.74 g,96%).

¹H-NMR (CDCl₃) δ: 6.99 (1H, d, J=9.6 Hz), 7.60 (1H, d, J=9.6 Hz).

Reference Example 131 6-Chloropyridazine-3-sulfonyl fluoride

To a mixture cooled to −20° C. of methanol (10 mL) and water (10 mL)were added potassium hydrogenfluoride (16 g) and6-chloropyridazine-3-thiol (2.37 g). After stirring at the sametemperature for 20 min, chlorine was blown in for 30 min. Ice water (20mL) was added and the precipitate was collected by filtration. Water wasadded to the precipitate and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure to allow crystallization, and the crystals were washed withhexane to give the title compound as a gray solid (yield 1.68 g, 53%).

¹H-NMR (CDCl₃) δ: 7.86-7.89 (1H, m), 8.17-8.19 (1H, m).

Reference Example 132 Pyridin-3-ylsulfonyl chloride hydrochloride

A mixture of 3-pyridinesulfonic acid (50.0 g), phosphorus pentachloride(80.0 g) and phosphorus oxychloride (100 mL) was stirred at 120° C. for8 hr. Under a nitrogen atmosphere, the mixture was cooled to roomtemperature, and chloroform (dehydrated, 330 mL) was added. Hydrogenchloride was blown in, and the precipitated crystals were collected byfiltration and washed with chloroform (dehydrated) to give the titlecompound as a white solid (yield 54.7 g, 81%).

¹H-NMR (DMSO-d₆) δ: 8.03-8.07 (1H, m), 8.68 (1H, d, J=8.1 Hz), 8.87 (1H,d, J=5.7 Hz), 9.01 (1H, s).

Reference Example 133 6-Methoxypyridin-3-ylsulfonyl chloride

5-Amino-2-methoxypyridine (1.24 g) was dissolved in acetic acid (8.3mL), and the mixture was stirred under ice-cooling. Concentratedhydrochloric acid (8.3 mL) was added, and an aqueous solution (5 mL) ofsodium nitrite (689 mg) was added dropwise over 15 min while keeping theinside temperature at not higher than 10° C. The reaction mixture wasstirred for 10 min, and gradually added at 5° C. to a mixture of cuprouschloride (280 mg) and acetic acid (17 ml) saturated in advance withsulfur dioxide gas. The mixture was allowed to gradually warm to roomtemperature until the generation of gas stopped. The reaction mixturewas concentrated to about 5 mL under reduced pressure, and theprecipitate was collected by filtration to give the title compound(yield 1.0 g, 51%) as crude crystals. This compound was used for thenext reaction without purification.

Reference Example 134 6-Chloropyridin-3-ylsulfonyl chloride

Under ice-cooling, thionyl chloride (12 mL) was added dropwise over 1 hrto water (70 mL) and the mixture was stirred at room temperature for 12hr to give a sulfur dioxide-containing solution. Under ice-cooling,5-amino-2-chloropyridine (5.0 g) was added to concentrated hydrochloricacid (40 mL) and the mixture was stirred. An aqueous solution (12.5 mL)of sodium nitrite (2.88 g) was added dropwise while keeping the insidetemperature at not higher than 5° C., and the mixture was furtherstirred for 15 min. The reaction mixture was gradually added at 5° C. tothe above-mentioned sulfur dioxide-containing solution added withcuprous chloride (70 mg). Under ice-cooling, the mixture was furtherstirred for 30 min. The precipitate was collected by filtration, andwashed with water and ethanol to give the title compound (yield 4.79 g,58%).

¹H-NMR (CDCl₃) δ: 7.60-7.63 (1H, m), 8.24-8.27 (1H, m), 9.03-9.04 (1H,m).

Reference Example 135 2-Chloro-3-pyridinesulfonyl chloride

Under ice-cooling, thionyl chloride (24 mL) was added dropwise over 1 hrto water (140 mL) and the mixture was stirred at room temperature for 12hr to give a sulfur dioxide-containing solution. Under ice-cooling,5-amino-2-chloropyridine (10 g) was added to concentrated hydrochloricacid (80 mL) and the mixture was stirred. An aqueous solution (25 mL) ofsodium nitrite (5.75 g) was added dropwise while keeping the insidetemperature at not higher than 5° C., and the mixture was furtherstirred for 15 min. The reaction mixture was gradually added at 5° C. tothe above-mentioned sulfur dioxide-containing solution added withcuprous chloride (140 mg). Under ice-cooling, the mixture was furtherstirred for 30 min, and the precipitate was collected by filtration andwashed with water and ethanol to give the title compound (yield 6.99 g,42%).

¹H-NMR (CDCl₃) δ: 7.54-7.56 (1H, m), 8.46-8.48 (1H, m), 8.71-8.73 (1H,m).

Reference Example 136 6-Chloro-5-methylpyridine-3-amine

Reduced iron (793 mg) was added to an aqueous solution (25 mL) ofammonium chloride (1.27 g), and the mixture was stirred at roomtemperature for 5 min. A solution (10 mL) of2-chloro-3-methyl-5-nitropyridine (816 mg) in methanol was addeddropwise over 10 min. The reaction mixture was stirred at 40° C. for 20min and at 50° C. for 1.5 hr and further refluxed under heating for 1hr. The reaction mixture was filtered through celite, and celite waswashed with methanol. Methanol was mostly removed by concentrated underreduced pressure, and saturated aqueous sodium hydrogencarbonatesolution was added. The mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=19:1→7:3) to give the title compound as a solid (yield 280 mg,42%).

¹H-NMR (CDCl₃) δ: 2.29 (3H, s), 3.62 (2H, br), 6.88-6.89 (1H, m),7.70-7.71 (1H, m).

Reference Example 137 6-Chloro-5-methylpyridine-3-sulfonyl chloride

Under ice-cooling, thionyl chloride (0.6 mL) was added dropwise over 30min to water (3.4 mL). The mixture was stirred at room temperature for12 hr to give a sulfur dioxide-containing solution. Under ice-cooling,6-chloro-5-methylpyridine-3-amine (278 mg) was added to concentratedhydrochloric acid (6 mL) and the mixture was stirred. An aqueoussolution (2 mL) of sodium nitrite (148 mg) was added dropwise whilekeeping the inside temperature at not higher than 5° C., and the mixturewas further stirred for 15 min. The reaction mixture was gradually addedat 5° C. to the above-mentioned sulfur dioxide-containing solution addedwith cuprous chloride (5 mg). Under ice-cooling, the mixture was furtherstirred for 30 min, and the precipitate was collected by filtration andwashed with water to give the title compound as a pale-yellow solid(yield 271 mg, 62%).

¹H-NMR (CDCl₃) δ: 2.54 (3H, s), 8.15 (1H, s), 8.86 (1H, s).

Reference Example 138 2-Pyridinesulfonyl chloride

Under ice-cooling, 2-mercaptopyridine (2.0 g) was added to sulfuric acid(50 mL). To the mixture was added dropwise an aqueous sodiumhypochlorite solution (chlorine content 5%, 126 mL) over 1.5 hr, and themixture was further stirred at the same temperature for 30 min. Thereaction mixture was diluted with water (100 mL), and extracted withdichloromethane. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure togive the title compound as a colorless oil (yield 2.45 g, 77%).

¹H-NMR (CDCl₃) δ: 7.69-7.71 (1H, m), 8.06-8.14 (2H, m), 8.83-8.85 (1H,m).

Reference Example 139 Ethyl2-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate

By a similar operation as in Reference Example 41 and using ethyl2-methyl-1H-pyrrole-3-carboxylate (8.81 g), sodium hydride (60% in oil,2.58 g) and benzenesulfonyl chloride (7.8 mL), the title compound wasobtained as white crystals (yield 14.3 g, 85%).

¹H-NMR (CDCl₃) δ: 1.31 (3H, t, J=7.2 Hz), 2.62 (3H, s), 4.24 (2H, q,J=7.2 Hz), 6.63 (1H, d, J=3.3 Hz), 7.30 (1H, d, J=3.3 Hz), 7.51-7.57(2H, m), 7.62-7.68 (1H, m), 7.81-7.84 (2H, m).

Reference Example 140 Methyl5-bromo-4-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate

Sodium hydride (60% in oil, 202 mg) was washed with hexane and suspendedin N,N-dimethylformamide (10 mL). A solution (10 mL) of methyl5-bromo-4-methyl-1H-pyrrole-3-carboxylate (1.0 g) inN,N-dimethylformamide was added dropwise at −78° C. After completion ofthe dropwise addition, the reaction mixture was stirred at roomtemperature for 30 min and added dropwise to an ice-cooled solution (10mL) of benzenesulfonyl chloride (0.71 mL) in N,N-dimethylformamide.After completion of the dropwise addition, the reaction mixture wasstirred at room temperature for 1 hr, and concentrated under reducedpressure. The residue was recrystallized from ethyl acetate-hexane togive the title compound as a brown solid (yield 1.13 g, 69%).

¹H-NMR (CDCl₃) δ: 2.11 (3H, s), 3.79 (3H, s), 7.45-7.70 (3H, m),7.85-7.95 (2H, m), 8.06 (1H, s).

Reference Example 141 Methyl5-bromo-1-[(3-chlorophenyl)sulfonyl]-4-methyl-1H-pyrrole-3-carboxylate

Sodium hydride (60% in oil, 202 mg) was washed with hexane, added toN,N-dimethylformamide solution (10 mL), and a solution (10 mL) of methyl5-bromo-4-methyl-1H-pyrrole-3-carboxylate (1.0 g) inN,N-dimethylformamide was added dropwise at −78° C. After completion ofthe dropwise addition, the reaction mixture was stirred at roomtemperature for 30 min, and added dropwise to an ice-cooled solution (10mL) of 3-chlorobenzenesulfonyl chloride (0.78 mL) inN,N-dimethylformamide. After completion of the dropwise addition, thereaction mixture was stirred at room temperature for 1 hr andconcentrated under reduced pressure. The residue was recrystallized fromethyl acetate-hexane to give the title compound as a brown solid (yield1.00 g, 56%).

¹H-NMR (CDCl₃) δ: 2.17 (3H, s), 3.84 (3H, s), 7.50 (1H, t, J=8.0 Hz),7.60-7.70 (1H, m), 7.80-7.90 (1H, m), 7.94 (1H, m), 8.08 (1H, s).

Reference Example 142 Ethyl5-bromo-4-methyl-1-[(3-methylphenyl)sulfonyl]-1H-pyrrole-3-carboxylate

Under an argon atmosphere, sodium hydride (60% in oil, 452 mg) wassuspended in N,N-dimethylformamide (10 mL), and a solution (10 mL) ofethyl 5-bromo-4-methyl-1H-pyrrole-3-carboxylate (2.20 g) inN,N-dimethylformamide was added dropwise at −78° C. over 30 min. Themixture was stirred at room temperature for 30 min, and added dropwiseto an ice-cooled solution (10 mL) of (3-methylbenzene)sulfonyl chloride(1.64 mL) in N,N-dimethylformamide over 10 min. The reaction mixture wasstirred at room temperature for 1 hr, water was added, and the mixturewas extracted with ethyl acetate. The extract was washed with water andsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=9:1→1:1), andrecrystallized from diethyl ether to give the title compound as acolorless solid (yield 3.02 g, 83%).

¹H-NMR (CDCl₃) δ: 1.36 (3H, t, J=7.2 Hz), 2.16 (3H, s), 2.44 (3H, s),4.29 (2H, dd, J=7.2 Hz, 14.4 Hz), 7.43-7.37 (2H, m), 7.57-7.78 (2H, m),8.10 (1H, s).

Reference Example 143 Methyl5-bromo-1-[(4-fluorophenyl)sulfonyl]-4-methyl-1H-pyrrole-3-carboxylate

Under an argon atmosphere, to a suspension of sodium hydride (60% inoil, 405 mg) in N,N-dimethylformamide (10 mL) was added dropwise asolution (10 mL) of methyl 5-bromo-4-methyl-1H-pyrrole-3-carboxylate(1.84 g) in N,N-dimethylformamide at −78° C. over 30 min. The mixturewas stirred at room temperature for 30 min and added dropwise to anice-cooled solution (10 mL) of (4-fluorobenzene)sulfonyl chloride (1.97g) in N,N-dimethylformamide over 10 min. The reaction mixture wasstirred at room temperature for 1 hr, water was added, and the mixturewas extracted with ethyl acetate. The extract was washed with water andsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=9:1→3:2), andthe obtained solid was washed with hexane-diethyl ether (1:1) to givethe title compound as a colorless solid (yield 2.21 g, 70%).

¹H-NMR (CDCl₃) δ: 2.16 (3H, s), 3.83 (3H, s), 7.20-7.26 (2H, m),7.97-8.02 (2H, m), 8.08 (1H, s).

Reference Example 144 Methyl5-bromo-4-ethyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate

Using sodium hydride (60% in oil, 393 mg), methyl5-bromo-4-ethyl-1H-pyrrole-3-carboxylate (2.00 g) and benzenesulfonylchloride (1.25 mL), a procedure as in Reference Example 41 was performedto give the title compound as white crystals (yield 2.93 g, 91%).

¹H-NMR (CDCl₃) δ: 1.05 (3H, t, J=7.5 Hz), 2.62 (2H, q, J=7.5 Hz), 3.83(3H, s), 7.54-7.59 (2H, m), 7.65-7.71 (1H, m), 7.95-7.98 (1H, m), 8.11(1H, s).

Reference Example 145 Methyl5-bromo-4-isopropyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate

Using methyl 5-bromo-4-isopropyl-1H-pyrrole-3-carboxylate (3.29 g),sodium hydride (60% in oil, 708 mg), and benzenesulfonyl chloride (2.60g), a procedure as in Reference Example 41 was performed to give thetitle compound as a pale-yellow oil (yield 4.8 g, 93%).

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=7.2 Hz), 3.26-3.36 (1H, m), 3.82 (3H,s), 7.54-7.60 (2H, m), 7.66-7.72 (1H, m), 7.94-7.98 (2H, m), 8.13 (1H,s).

Reference Example 146 Methyl5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate

Sodium hydride (60% in oil, 1.60 g) was washed twice with hexane andsuspended in tetrahydrofuran (20 mL). Under ice-cooling, a solution (10mL) of methyl 5-bromo-1H-pyrrole-3-carboxylate (2.67 g) intetrahydrofuran was added dropwise, and the mixture was stirred at thesame temperature for 10 min. 15-Crown-5 (8.83 g) andpyridin-3-ylsulfonyl chloride hydrochloride (4.21 g) were added to thereaction mixture, and the mixture was further stirred at roomtemperature for 12 hr. Water was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed withsaturated aqueous sodium hydrogencarbonate solution, water and saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was recrystallized from ethylacetate-hexane to give the title compound as white crystals (yield 4.21g, 93%).

¹H-NMR (CDCl₃) δ: 3.84 (3H, s), 6.72 (1H, d, J=1.8 Hz), 7.51-7.56 (1H,m), 8.08 (1H, d, J=1.8 Hz), 8.22-8.26 (1H, m), 8.90-8.92 (1H, m),9.20-9.21 (1H, m).

Reference Example 147 Methyl5-bromo-1-{[3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrole-3-carboxylate

Using methyl 5-bromo-1H-pyrrole-3-carboxylate (2.89 g), sodium hydride(60% in oil, 850 mg), 15-crown-5 (4.69 g) and3-methylsulfonylbenzenesulfonyl chloride (4.38 g), a procedure as inReference Example 146 was performed to give the title compound as whitecrystals (yield 5.50 g, 92%).

¹H-NMR (CDCl₃) δ: 3.11 (3H, s), 3.84 (3H, s), 6.72 (1H, d, J=2.1 Hz),7.83 (1H, t, J=7.8 Hz), 8.07 (1H, d, J=2.1 Hz), 8.22-8.28 (2H, m), 8.59(1H, t, J=1.8 Hz).

Reference Example 148 Ethyl5-bromo-2-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate

Ethyl 5-bromo-2-methyl-1H-pyrrole-3-carboxylate (2.26 g) was dissolvedin tetrahydrofuran (100 mL), sodium hydride (60% in oil, 1.16 g) wasadded and the mixture was stirred at room temperature for 15 min.15-Crown-5 (5.90 mL) was added and the mixture was further stirred atthe same temperature for 15 min, and 3-pyridinesulfonyl chloridehydrochloride (3.13 g) was added. The reaction mixture was stirred atroom temperature for 1 hr, saturated aqueous sodium hydrogencarbonatesolution was added, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluent: hexane-ethylacetate=19:1→7:3) to give the title compound as a yellow oil (yield 2.31g, 64%).

¹H-NMR (CDCl₃) δ: 1.24-1.34 (3H, m), 2.94 (3H, s), 4.23-4.30 (2H, m),6.69 (1H, s), 7.51-7.55 (1H, m), 8.17-8.21 (1H, m), 8.88-8.91 (1H, m),9.14 (1H, m).

Reference Example 149 Ethyl1-[(3-chlorophenyl)sulfonyl]-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate

Using ethyl 2-methyl-5-phenyl-1H-pyrrole-3-carboxylate (1.53 g), sodiumhydride (60% in oil, 303 mg) and 3-chlorobenzenesulfonyl chloride (848mg), a procedure as in Reference Example 41 was performed to give thetitle compound as a brown oil (yield 800 mg, 30%).

¹H-NMR (CDCl₃) δ: 1.32 (3H, t, J=7.2 Hz), 2.90 (3H, s), 4.29 (2H, q,J=7.2 Hz), 6.50 (1H, s), 7.13-7.56 (9H, m).

Reference Example 150 Ethyl2-methyl-1-[(3-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate

To a solution (10 mL) of ethyl2-methyl-5-phenyl-1H-pyrrole-3-carboxylate (630 mg) in tetrahydrofuranwas added sodium hydride (60% in oil, 73 mg) after washing with hexane,and the mixture was stirred at room temperature for 15 min.3-Methylbenzenesulfonyl chloride (0.479 mL) was added to the reactionmixture, and the mixture was stirred at room temperature for 18 hr.Water was added to the reaction mixture, and the mixture was extractedwith ethyl acetate. The extract was washed with saturated brine, driedover anhydrous sodium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=9:1→2:1) to give the titlecompound as a brown oil (yield 254 mg, 24%).

¹H-NMR (CDCl₃) δ: 1.20-1.40 (3H, m), 2.31 (3H, s), 2.89 (3H, s),4.20-4.40 (2H, m), 6.47 (1H, s), 7.10-7.50 (9H, m).

Reference Example 151 Ethyl5-phenyl-1-{[4-(trifluoromethoxy)phenyl]sulfonyl}-1H-pyrrole-3-carboxylate

Sodium hydride (60% in oil, 0.20 g) was added to a solution (20 mL) ofethyl 5-phenyl-1H-pyrrole-3-carboxylate (0.71 g) in tetrahydrofuranunder ice-cooling. After stirring at the same temperature for 15 min,[4-(trifluoromethoxy)benzene]sulfonyl chloride (1.00 g) was added, andthe mixture was stirred at room temperature for 4 hr. Water was added tothe reaction mixture, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluent: hexane-ethylacetate=7:2) to give the title compound as an oil (yield 1.36 g, 94%).

¹H-NMR (CDCl₃) δ: 1.36 (3H, t, J=7.1 Hz), 4.32 (2H, q, J=7.1 Hz), 6.56(1H, s), 7.13 (4H, dd, J=13.0 Hz), 7.28-7.42 (5H, m), 8.08 (1H, d, J=1.9Hz).

Reference Example 152 Ethyl5-phenyl-1-(2-thienylsulfonyl)-1H-pyrrole-3-carboxylate

To a solution (20 mL) of ethyl 5-phenyl-1H-pyrrole-3-carboxylate (440mg) in tetrahydrofuran was added sodium hydride (60% in oil, 123 mg) atroom temperature and the mixture was stirred for 30 min. 15-Crown-5 (675mg) was added dropwise and the mixture was stirred for 30 min.2-Thiophenesulfonyl chloride (485 mg) was added, and the mixture wasfurther stirred for 1 hr. Saturated brine was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (eluent: hexane-ethylacetate=19:1→7:3), and crystallized from diisopropyl ether.hexane togive the title compound as colorless crystals (yield 710 mg, 96%).

¹H-NMR (CDCl₃) δ: 1.36 (3H, t, J=7.2 Hz), 4.31 (2H, q, J=7.2 Hz), 6.56(1H, d, J=1.8 Hz), 6.89 (1H, dd, J=3.9, 4.9 Hz), 7.07 (1H, dd, J=1.3,3.9 Hz), 7.24-7.43 (5H, m), 7.58 (1H, dd, J=1.3, 4.9 Hz), 8.04 (1H, d,J=1.8 Hz).

Reference Example 153 Ethyl1-[(2-chloro-5-pyrimidine)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate

Ethyl 5-phenyl-1H-pyrrole-3-carboxylate (1.60 g) was dissolved intetrahydrofuran (50 mL), sodium hydride (60% in oil, 446 mg) was addedand the mixture was stirred at room temperature for 15 min. 15-Crown-5(2.24 mL) was added and the mixture was further stirred at the sametemperature for 15 min. 2-Chloro-5-pyrimidinesulfonyl chloride (2.06 g)was added and the reaction mixture was stirred at room temperature for 1hr. Water was added, and the mixture was extracted with ethyl acetate.The extract was washed with water and saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→7:3) to give the title compound as a yellowoil (yield 2.03 g, 70%).

¹H-NMR (CDCl₃) δ: 1.35-1.39 (3H, m), 4.30-4.37 (2H, m), 6.64 (1H, s),7.22-7.26 (2H, m), 7.37-7.51 (3H, m), 8.04 (1H, s), 8.37 (2H, s).

Reference Example 154 Ethyl1-[(2-methyl-5-pyrimidine)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate

Under a nitrogen atmosphere, tetrakis(triphenylphosphine)palladium (87mg) and 2 mol/L trimethylaluminum-hexane solution (1.5 mL) were added toa solution of ethyl1-[(2-chloro-5-pyrimidine)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate(588 mg) in tetrahydrofuran (20 mL) with stirring. The mixture wasstirred at room temperature for 15 min and 2 mol/Ltrimethylaluminum-hexane solution (1 mL) was added. After stirring atthe same temperature for 20 min, ice water (100 mL) and ammoniumchloride (2.0 g) were added, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→1:1) to give the title compound as apale-yellow oil (yield 350 mg, 63%).

¹H-NMR (CDCl₃) δ: 1.34-1.39 (3H, m), 2.77 (3H, s), 4.29-4.36 (2H, m),6.61 (1H, s), 7.21-7.26 (2H, m), 7.37-7.49 (3H, m), 8.06 (1H, s), 8.41(2H, s).

Reference Example 155 Ethyl1-[(2-amino-5-pyrimidine)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate

A 7 mol/L ammonia-methanol solution (1.0 mL) was added to a solution ofethyl1-[(2-chloro-5-pyrimidine)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate(392 mg) in tetrahydrofuran (10 mL) with stirring. The mixture wasstirred at room temperature for 20 min, saturated aqueous sodiumhydrogencarbonate solution was added, and the mixture was extracted withethyl acetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure togive the title compound as a colorless solid (yield 373 mg, about 100%).

¹H-NMR (CDCl₃) δ: 1.34-1.39 (3H, m), 4.28-4.36 (2H, m), 5.60 (2H, br),6.59 (1H, s), 7.26-7.46 (5H, m), 8.02-8.03 (3H, m).

Reference Example 156 Ethyl1-(imidazo[1,2-a]pyrimidin-6-ylsulfonyl)-5-phenyl-1H-pyrrole-3-carboxylate

A mixture of ethyl1-[(2-amino-5-pyrimidine)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate(373 mg), 2-bromo-1,1-diethoxyethane (394 mg) and acetic acid (20 mL)was stirred in a microwave reaction apparatus at 130° C. for 30 min.After cooling to room temperature, the solvent was evaporated underreduced pressure. Saturated aqueous sodium hydrogencarbonate solutionwas added to the residue, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→ethyl acetate) to give the title compound as abrown solid (yield 157 mg, 40%).

¹H-NMR (CDCl₃) δ: 1.35-1.40 (3H, m), 4.30-4.37 (2H, m), 6.61 (1H, s),7.17-7.49 (2H, m), 7.26-7.49 (4H, m), 7.94 (1H, s), 7.99 (1H, s), 8.11(1H, s), 8.38 (1H, s).

Reference Example 157 Ethyl1-(pyridazin-3-ylsulfonyl)-5-phenyl-1H-pyrrole-3-carboxylate

Ethyl 5-phenyl-1H-pyrrole-3-carboxylate (1.06 g) was dissolved intetrahydrofuran (30 mL), sodium hydride (60% in oil, 300 mg) was addedand the mixture was stirred at room temperature for 15 min. 15-Crown-5(1.52 mL) was added and the mixture was further stirred at the sametemperature for 15 min. 6-Chloropyridazine-3-sulfonyl fluoride (1.28 g)was added and the reaction mixture was stirred at room temperature for30 min. Hydrazine (1.60 g) was added and the reaction mixture wasstirred at room temperature for 15 min. Saturated aqueous sodiumhydrogencarbonate solution was added, and the mixture was extracted withethyl acetate. The extract was washed with water and saturated brine,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was dissolved in tetrahydrofuran (30 mL),manganese dioxide (75% chemically treated product, 5.0 g) was added, andthe mixture was stirred at room temperature for 10 min. The reactionmixture was filtered through celite, and celite was washed with ethylacetate. The filtrate was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→1:1) to give the title compound (yield 613 mg,24%).

¹H-NMR (CDCl₃) δ: 1.34-1.39 (3H, m), 4.29-4.36 (2H, m), 6.61 (1H, s),7.11-7.22 (2H, m), 7.24-7.51 (5H, m), 8.20 (1H, s), 9.28-9.30 (1H, s).

Reference Example 158 Ethyl2,4-dimethyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate

Using ethyl 2,4-dimethyl-5-phenyl-1H-pyrrole-3-carboxylate (3.0 g),sodium hydride (60% in oil, 596 mg) and benzenesulfonyl chloride (1.92mL), a procedure as in Reference Example 4 was performed to give thetitle compound as a brown oil (yield 506 mg, 37%).

¹H-NMR (CDCl₃) δ: 1.35 (3H, t, J=7.2 Hz), 1.89 (3H, s), 2.85 (3H, s),4.30 (2H, q, J=7.2 Hz), 7.07-7.46 (9H, m), 7.51-7.58 (1H, m).

Reference Example 159 Ethyl2-methyl-1-(phenylsulfonyl)-5-(3-thienyl)-1H-pyrrole-3-carboxylate

Using ethyl 2-methyl-5-(3-thienyl)-1H-pyrrole-3-carboxylate (1.25 g),sodium hydride (60% in oil, 255 mg) and benzenesulfonyl chloride (1.22mL), a procedure as in Reference Example 4 was performed to give thetitle compound as white crystals (yield 0.80 g, 40%).

¹H-NMR (CDCl₃) δ: 1.29-1.57 (3H, m), 2.87-2.90 (3H, m), 4.22-4.37 (2H,m), 6.50-6.95 (1H, m), 7.06-7.19 (1H, m), 7.24-7.29 (2H, m), 7.36-7.46(4H, m), 7.52-7.58 (1H, m).

Reference Example 160 Ethyl5-(4-fluorophenyl)-2-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate

Ethyl 5-(4-fluorophenyl)-2-methyl-1H-pyrrole-3-carboxylate (4.95 g) wasdissolved in absolute tetrahydrofuran (50 mL), and sodium hydride (60%in oil, 1.20 g) was added under ice-cooling. The mixture was stirred atroom temperature for 15 min, and benzenesulfonyl chloride (5.30 g) wasadded dropwise. The reaction mixture was stirred at room temperature for18 hr, ice water was added and the mixture was extracted with ethylacetate. The extract was washed with water, dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=7:2) to give the title compound as a solid(yield 2.75 g, 35%).

¹H-NMR (CDCl₃) δ: 1.34 (3H, t, J=7.1 Hz), 2.88 (3H, s), 4.26 (2H, q,J=7.1 Hz), 6.46 (1H, s), 6.96-7.27 (3H, m), 7.33-7.47 (5H, m), 7.51-7.66(1H, m).

Reference Example 161 Methyl5-phenyl-1-(phenylsulfonyl)-4-propyl-1H-pyrrole-3-carboxylate

Using methyl 5-phenyl-4-propyl-1H-pyrrole-3-carboxylate (2.0 g), sodiumhydride (60% in oil, 434 mg) and benzenesulfonyl chloride (1.60 g), aprocedure as in Reference Example 4 was performed to give the titlecompound as colorless crystals (yield 2.73 g, 69%).

¹H-NMR (CDCl₃) δ: 0.72 (3H, t, J=7.5 Hz), 1.32-1.41 (2H, m), 2.31-2.36(2H, m), 3.85 (3H, s), 6.94-6.97 (2H, m), 7.24-7.40 (7H, m), 7.51-7.56(1H, m), 8.09 (1H, s).

Reference Example 162 Methyl4,5-diphenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate

Using methyl 4,5-diphenyl-1H-pyrrole-3-carboxylate (428 mg), sodiumhydride (60% in oil, 74 mg) and benzenesulfonyl chloride (0.24 mL), aprocedure as in Reference Example 4 was performed to give the titlecompound as white crystals (yield 506 mg, 79%).

¹H-NMR (CDCl₃) δ: 3.74 (3H, s), 6.87-6.92 (2H, m), 7.00-7.15 (7H, m),7.20-7.36 (5H, m), 7.49-7.58 (1H, m), 8.21 (1H, s).

Reference Example 163 Ethyl4-chloro-2-methyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate

Using ethyl 4-chloro-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate (509mg), sodium hydride (60% in oil, 139 mg) and benzenesulfonyl chloride(511 mg), a procedure as in Reference Example 4 was performed to givethe title compound as a pale-yellow oil (yield 610 mg, 78%).

¹H-NMR (CDCl₃) δ: 1.36 (3H, t, J=7.2 Hz), 2.85 (3H, s), 4.34 (2H, q,J=7.2 Hz), 7.15-7.19 (2H, m), 7.32-7.45 (7H, m), 7.56-7.61 (1H, m).

Reference Example 164 Ethyl2-chloro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate

To a solution (40 mL) of ethyl2-chloro-5-phenyl-1H-pyrrole-3-carboxylate (1.0 g) in tetrahydrofuranwas added sodium hydride (60% in oil, 488 mg) at room temperature andthe mixture was stirred for 30 min. 15-Crown-5 (2.65 g) was addeddropwise and the mixture was stirred for 30 min. Benzenesulfonylchloride (1.84 g) was added, and the mixture was further stirred for 24hr. Saturated brine was added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=85:15), and crystallizedfrom diisopropyl ether to give the title compound as colorless crystals(yield 1.27 g, 81%).

¹H-NMR (CDCl₃) δ: 1.31 (3H, t, J=7.2 Hz), 4.27 (2H, q, J=7.2 Hz), 6.55(1H, s), 7.38-7.50 (7H, m), 7.60-7.71 (3H, m).

Reference Example 165 Ethyl2-fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate

To a solution (20 mL) of ethyl2-fluoro-5-phenyl-1H-pyrrole-3-carboxylate (300 mg) in tetrahydrofuranwas added sodium hydride (60% in oil, 155 mg) at room temperature andthe mixture was stirred for 30 min. 15-Crown-5 (850 mg) was addeddropwise and the mixture was stirred for 30 min. Benzenesulfonylchloride (591 mg) was added, and the mixture was further stirred for 24hr. Saturated brine was added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=85:15) to give the titlecompound as a colorless oil (yield 390 mg, 81%).

¹H-NMR (CDCl₃) δ: 1.32 (3H, t, J=7.2 Hz), 4.28 (2H, q, J=7.2 Hz), 6.31(1H, d, J=5.1 Hz), 7.30-7.51 (7H, m), 7.61-7.67 (3H, m).

Reference Example 166 Ethyl2-chloro-4-fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate

To a solution (60 mL) of ethyl2-chloro-4-fluoro-5-phenyl-1H-pyrrole-3-carboxylate (330 mg) intetrahydrofuran was added sodium hydride (60% in oil, 296 mg) at roomtemperature and the mixture was stirred for 30 min. 15-Crown-5 (1.63 g)was added dropwise and the mixture was stirred for 30 min.Benzenesulfonyl chloride (1.13 g) was added, and the mixture was furtherstirred for 120 hr. Saturated brine was added to the reaction mixture,and the mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=9:1→8:2) to givethe title compound as a pale-yellow oil (yield 260 mg, 52%).

¹H-NMR (CDCl₃) δ: 1.30-1.38 (3H, m), 4.27-4.38 (2H, m), 7.31-7.54 (7H,m), 7.63-7.73 (3H, m).

Reference Example 167 Ethyl4-fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate

To a solution (10 mL) of ethyl4-fluoro-5-phenyl-1H-pyrrole-3-carboxylate (100 mg) in tetrahydrofuranwas added sodium hydride (60% in oil, 52 mg) at room temperature and themixture was stirred for 30 min. 15-Crown-5 (284 mg) was added dropwiseand the mixture was stirred for 30 min. Benzenesulfonyl chloride (151mg) was added, and the mixture was further stirred for 1 hr. Saturatedbrine was added to the reaction mixture, and the mixture was extractedwith ethyl acetate. The extract was washed with saturated brine, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=9:1) to give the title compound as acolorless oil (yield 60 mg, 38%).

¹H-NMR (CDCl₃) δ: 1.37 (3H, t, J=7.2 Hz), 4.44 (2H, q, J=7.2 Hz),7.14-7.16 (2H, m), 7.28-7.59 (8H, m), 7.94 (1H, d, J=5.1 Hz).

Reference Example 168 Ethyl5-butyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate

Under an argon atmosphere, ethyl 5-butyl-1H-pyrrole-3-carboxylate (976mg) was dissolved in tetrahydrofuran (50 mL), sodium hydride (60% inoil, 240 mg) was added and the mixture was stirred at room temperaturefor 30 min. Benzenesulfonyl chloride (0.77 mL) was added, and themixture was stirred at room temperature for 1 hr. Water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluent: hexane-ethylacetate=19:1→8:2), and the obtained solid was washed with hexane to givethe title compound as a colorless solid (yield 780 mg, 47%).

¹H-NMR (CDCl₃) δ: 0.84-0.89 (3H, m), 1.26-1.37 (5H, m), 1.47-1.55 (2H,m), 2.59-2.64 (2H, m), 4.25-4.32 (2H, m), 6.37 (1H, m), 7.52-7.66 (3H,m), 7.79-7.82 (2H, m), 7.92 (1H, s).

Reference Example 169 Ethyl5-cyclohexyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate

Using ethyl 5-cyclohexyl-1H-pyrrole-3-carboxylate (530 mg), a procedureas in Reference Example 168 was performed to give the title compound asa colorless oil (yield 651 mg, 75%).

¹H-NMR (CDCl₃) δ: 1.15-1.76 (13H, m), 2.83 (1H, m), 4.25-4.32 (2H, m),6.40 (1H, s), 7.52-7.56 (2H, m), 7.60-7.66 (1H, m), 7.77-7.81 (2H, m),7.88 (1H, s).

Reference Example 170 Methyl4-methyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate

Methyl 5-bromo-4-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (1.1g), phenylboronic acid (487 mg), sodium carbonate (488 mg) andtetrakis(triphenylphosphine)palladium (355 mg) were suspended in amixture of 1,2-dimethoxyethane (10 mL) and distilled water (10 mL), andthe mixture was reacted in a microwave reactor (Emrys Optimizer,Personal Chemistry, 140° C., 4 min). The reaction mixture was filteredthrough celite, water was added to the filtrate and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=9:1→2:1) to give the titlecompound as a pale-yellow oil (yield 947 mg, 87%).

¹H-NMR (CDCl₃) δ: 1.98 (3H, s), 3.85 (3H, s), 6.98 (2H, d, J=8.4 Hz),7.20-7.60 (8H, m), 8.08 (1H, s).

Reference Example 171 Methyl1-[(3-chlorophenyl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carboxylate

Methyl5-bromo-1-[(3-chlorophenyl)sulfonyl]-4-methyl-1H-pyrrole-3-carboxylate(1.0 g), phenylboronic acid (403 mg), sodium carbonate (405 mg) andtetrakis(triphenylphosphine)palladium (295 mg) were suspended in amixture of 1,2-dimethoxyethane (10 mL) and distilled water (10 mL), andthe mixture was reacted in a microwave reactor (Emrys Optimizer,Personal Chemistry, 140° C., 4 min). The reaction mixture was filteredthrough celite, water was added to the filtrate, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=9:1→2:1) to give the titlecompound as a pale-brown oil (yield 724 mg, 73%).

¹H-NMR (CDCl₃) δ: 1.99 (3H, s), 3.86 (3H, s), 7.00 (2H, d, J=8.0 Hz),7.15-7.60 (7H, m), 8.05 (1H, s).

Reference Example 172 Ethyl4-methyl-1-[(3-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate

Under an argon atmosphere, a suspension of ethyl5-bromo-4-methyl-1-[(3-methylphenyl)sulfonyl]-1H-pyrrole-3-carboxylate(2.80 g), phenylboronic acid (1.84 g),tetrakis(triphenylphosphine)palladium (0.84 g), sodium carbonate (2.31g) in 1,2-dimethoxyethane (12 mL)-water (12 mL) was stirred at 70° C.for 12 hr. After cooling, the reaction mixture was filtered throughcelite, and celite was washed with ethyl acetate. The organic layer wasseparated from the filtrate, washed with water and saturated brine,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=9:1→7:3) to give the title compound as acolorless oil (yield 2.67 g, 96%).

¹H-NMR (CDCl₃) δ: 1.38 (3H, t, J=7.0 Hz), 1.98 (3H, s), 2.25 (3H, s),4.31 (2H, dd, J=7.0, 14.0 Hz), 6.99-7.39 (9H, m), 8.07 (1H, s).

Reference Example 173 Methyl1-[(4-fluorophenyl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carboxylate

Under an argon atmosphere, a suspension of methyl5-bromo-1-[(4-fluorophenyl)sulfonyl]-4-methyl-1H-pyrrole-3-carboxylate(2.10 g), phenylboronic acid (1.42 g),tetrakis(triphenylphosphine)palladium (0.65 g), sodium carbonate (1.77g) in 1,2-dimethoxyethane (11 mL)-water (11 mL) was stirred at 70° C.for 12 hr. After cooling, the reaction mixture was filtered throughcelite, and celite was washed with ethyl acetate. The organic layer wasseparated from the filtrate, washed with water and saturated brine,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=19:1→7:3) to give the title compound as acolorless oil (yield 1.75 g, 84%).

¹H-NMR (CDCl₃) δ: 1.99 (3H, s), 3.85 (3H, s), 6.95-7.42 (9H, m), 8.06(1H, s).

Reference Example 174 Ethyl2-methyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate

A suspension of ethyl5-bromo-2-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate (2.26g), phenylboronic acid (1.54 g),dichloro[bis(triphenylphosphine)]palladium (211 mg) and sodium carbonate(1.91 g) in 1,2-dimethoxyethane (20 mL)-water (10 mL) was stirred at 80°C. for 40 min. After cooling, the reaction mixture was filtered throughcelite, and celite was washed with ethyl acetate. The organic layer wasseparated from the filtrate, washed with water and saturated brine,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=9:1→6:4) to give the title compound as acolorless oil (yield 2.39 g, about 100%).

¹H-NMR (CDCl₃) δ: 1.30-1.34 (3H, m), 2.92 (3H, s), 4.23-4.30 (2H, m),6.59 (1H, s), 7.23-7.39 (4H, m), 7.50-7.68 (2H, m), 8.22-8.25 (1H, m),8.61-8.62 (1H, m), 8.75-8.77 (1H, m).

Reference Example 175 Methyl5-cyclopropyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate

Under an argon atmosphere, a suspension of methyl5-bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (2.11 g),cyclopropylboronic acid (683 mg), palladium(II) acetate (69 mg),tricyclohexylphosphine (174 mg) and tripotassium phosphate (4.55 g) intoluene (27 mL)-water (1.3 mL) was stirred at 100° C. for 4 hr. Aftercooling, the reaction mixture was diluted with water (50 mL), and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=19:1→8:2) togive the title compound as a yellow oil (yield 406 mg, 22%).

¹H-NMR (CDCl₃) δ: 0.30-0.36 (2H, m), 0.71-0.77 (2H, m), 2.00-2.08 (1H,m), 3.79 (3H, s), 6.19 (1H, s), 7.51-7.56 (2H, m), 7.63-7.66 (1H, m),7.85-7.88 (2H, m), 7.94 (1H, s).

Reference Example 176[2-methyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol

Using ethyl 2-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (8.05g) and a 1.5 mol/L solution (55 mL) of diisobutylaluminum hydride intoluene, a procedure as in Reference Example 5 was performed to give thetitle compound as white crystals (yield 6.61 g, 96%).

¹H-NMR (CDCl₃) δ: 1.37 (1H, brs), 2.29 (3H, s), 4.42 (2H, brs), 6.29(1H, d, J=3.6 Hz), 7.30 (1H, d, J=3.6 Hz), 7.49-7.55 (2H, m), 7.58-7.64(1H, m), 7.78-7.81 (2H, m).

Reference Example 177(5-Bromo-1-{[3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrol-3-yl)methanol

Using methyl5-bromo-1-{3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrole-3-carboxylate(5.41 g) and a 1.5 mol/L solution (26 mL) of diisobutylaluminum hydridein toluene, a procedure as in Reference Example 5 was performed to givethe title compound as white crystals (yield 4.83 g, 96%).

¹H-NMR (CDCl₃) δ: 1.66 (1H, t, J=8.1 Hz), 3.11 (3H, s), 4.52 (2H, d,J=8.1 Hz), 6.38 (1H, d, J=2.1 Hz), 7.33-7.45 (1H, m), 7.79 (1H, t, J=8.1Hz), 8.20-8.24 (2H, m), 8.53 (1H, t, J=1.8 Hz).

Reference Example 178[5-Bromo-4-ethyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol

Using methyl 5-bromo-4-ethyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate(1.35 g) and a 1.5 mol/L solution (7.5 mL) of diisobutylaluminum hydridein toluene, a procedure as in Reference Example 5 was performed to givethe title compound as a brown oil (yield 1.10 g, 88%).

¹H-NMR (CDCl₃) δ: 1.05 (3H, t, J=7.6 Hz), 2.39 (2H, q, J=7.6 Hz), 4.53(2H, s), 7.47-7.64 (4H, m), 7.90-7.95 (2H, m), 1H not detected.

Reference Example 179{1-[(3-Chlorophenyl)sulfonyl]-2-methyl-5-phenyl-1H-pyrrol-3-yl}methanol

Using ethyl1-[(3-chlorophenyl)sulfonyl]-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate(0.80 g) and a 1.5 mol/L solution (4.0 mL) of diisobutylaluminum hydridein toluene, a procedure as in Reference Example 5 was performed to givethe title compound as a brown oil (yield 345 mg, 48%).

¹H-NMR (CDCl₃) δ: 1.36 (1H, t, J=5.4 Hz), 2.53 (3H, s), 4.49 (2H, d,J=5.4 Hz), 6.20 (1H, s), 7.26-7.38 (8H, m), 7.47-7.51 (1H, m).

Reference Example 180(5-Phenyl-1-{[4-(trifluoromethoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl)methanol

A solution (30 mL) of ethyl5-phenyl-1-{[4-(trifluoromethoxy)phenyl]sulfonyl}-1H-pyrrole-3-carboxylate(1.33 g) in tetrahydrofuran was cooled to −78° C., a 1.5 mol/L solution(8.0 mL) of diisobutylaluminum hydride in toluene was added dropwise,and the mixture was further stirred at −78° C. for 3 hr. 1 mol/Lhydrochloric acid (20 mL) was added to the reaction mixture, and themixture was diluted with ethyl acetate. Insoluble material was filteredthrough celite, and the filtrate was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=3:2) to give the title compound as an oil (yield 0.71 g, 59%).

¹H-NMR (CDCl₃) δ: 1.56 (1H, s), 4.58 (2H, s), 6.22 (1H, s), 7.11 (2H,dd, J=0.85, 8.95 Hz), 7.17-7.22 (2H, m), 7.27-7.39 (5H, m), 7.42-7.43(1H, m).

Reference Example 181[5-Phenyl-1-(2-thienylsulfonyl)-1H-pyrrol-3-yl]methanol

A solution (20 mL) of ethyl5-phenyl-1-(2-thienylsulfonyl)-1H-pyrrole-3-carboxylate (650 mg) intetrahydrofuran was cooled to −70° C., and a 1.5 mol/L solution (5 mL)of diisobutylaluminum hydride in toluene was added dropwise by smallportions. The mixture was further stirred at −70° C. for 1 hr, 1 mol/Lhydrochloric acid (20 mL) was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=7:3→1:1) to givethe title compound as a pale-red oil (yield 480 mg, 84%).

¹H-NMR (CDCl₃) δ: 4.57 (2H, d, J=5.6 Hz), 6.23 (1H, d, J=1.8 Hz), 6.89(1H, dd, J=3.9, 4.9 Hz), 7.09 (1H, dd, J=1.4, 3.9 Hz), 7.28-7.41 (6H,m), 7.53 (1H, dd, J=1.4, 4.9 Hz).

Reference Example 182[2-Methyl-1-(phenylsulfonyl)-5-(3-thienyl)-1H-pyrrol-3-yl]methanol

Using methyl2-methyl-1-(phenylsulfonyl)-5-(3-thienyl)-1H-pyrrole-3-carboxylate (0.75g) and a 1.5 mol/L solution (4.0 mL) of diisobutylaluminum hydride intoluene, a procedure as in Reference Example 5 was performed to give thetitle compound as a brown oil (yield 0.42 g, 63%).

¹H-NMR (CDCl₃) δ: 1.35 (3H, t, J=5.4 Hz), 2.53 (3H, s), 4.48 (2H, d,J=5.4 Hz), 6.19 (1H, s), 7.06-7.10 (2H, m), 7.22-7.26 (1H, m), 7.35-7.44(4H, m), 7.49-7.54 (1H, m).

Reference Example 183[5-(4-Fluorophenyl)-2-methyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol

Ethyl5-(4-fluorophenyl)-2-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate(2.70 g) was dissolved in tetrahydrofuran (30 mL), and the mixture wascooled to −78° C. A 1.5 mol/L toluene solution (13.1 mL) ofdiisobutylaluminum hydride was added dropwise, and the mixture wasfurther stirred at −78° C. for 2 hr. 1 mol/L Hydrochloric acid (15 mL)was added to the reaction mixture, and the mixture was diluted withethyl acetate. The insoluble material was filtered through celite, andthe filtrate was extracted with ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=2:3) to give thetitle compound as an oil (yield 1.09 g, 45%).

¹H-NMR (CDCl₃) δ: 2.51 (3H, s), 4.47 (2H, s), 6.15 (1H, s), 7.00 (2H, t,J=8.7 Hz), 7.14-7.27 (2H, m), 7.35-7.43 (4H, m), 7.48-7.61 (1H, m).

Reference Example 184[2,4-Dimethyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol

Using ethyl2,4-dimethyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (1.01g) and a 1.5 mol/L solution (6.0 mL) of diisobutylaluminum hydride intoluene, a procedure as in Reference Example 5 was performed to give thetitle compound as a brown oil (yield 0.84 g, 94%).

¹H-NMR (CDCl₃) δ: 1.22 (3H, t, J=4.8 Hz), 1.83 (3H, s), 2.56 (3H, s),4.49 (2H, d, J=4.8 Hz), 7.11-7.43 (9H, m), 7.49-7.55 (1H, m).

Reference Example 185[5-Phenyl-1-(phenylsulfonyl)-4-propyl-1H-pyrrol-3-yl]methanol

Using methyl5-phenyl-1-(phenylsulfonyl)-4-propyl-1H-pyrrole-3-carboxylate (3.0 g),and a 1.5 mol/L solution (16.1 mL) of diisobutylaluminum hydride intoluene, a procedure as in Reference Example 5 was performed to give thetitle compound as a pale-red oil (yield 2.73 g, 95%).

¹H-NMR (CDCl₃) δ: 0.71 (3H, t, J=7.5 Hz), 1.26-1.50 (3H, m), 2.05-2.19(2H, m), 4.59 (2H, d, J=4.8 Hz), 6.99-7.02 (2H, m), 7.24-7.36 (7H, m),7.43 (1H, s), 7.48-7.52 (1H, m).

Reference Example 186[4,5-Diphenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol

Using methyl 4,5-diphenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate(439 mg) and a 1.5 mol/L solution (3.2 mL) of diisobutylaluminum hydridein toluene, a procedure as in Reference Example 5 was performed to givethe title compound as a brown oil (yield 361 mg, 88%).

¹H-NMR (CDCl₃) δ: 1.50 (1H, t, J=5.7 Hz), 4.49 (2H, d, J=5.7 Hz),6.96-6.99 (2H, m), 7.04-7.07 (2H, m), 7.11-7.18 (5H, m), 7.23-7.37 (5H,m), 7.48-7.53 (1H, m), 7.60 (1H, s).

Reference Example 187[2-Chloro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol

A solution (30 mL) of ethyl2-chloro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (1.27 g)in tetrahydrofuran was cooled to −70° C., a 1.5 mol/L solution (7.6 mL)of diisobutylaluminum hydride in toluene was added dropwise by smallportions. The mixture was further stirred at −70° C. for 1 hr, 1 mol/lhydrochloric acid (20 mL) was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=7:3→1:1) to givethe title compound as pale-red crystals (yield 882 mg, 78%).

¹H-NMR (CDCl₃) δ: 4.47 (2H, s), 6.27 (1H, s), 7.39-7.47 (7H, m),7.57-7.65 (3H, m).

Reference Example 188[2-Fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol

A solution (20 mL) of ethyl2-fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (390 mg)in tetrahydrofuran was cooled to −70° C., and a 1.5 mol/L solution (3.5mL) of diisobutylaluminum hydride in toluene was added dropwise by smallportions. The mixture was further stirred at −70° C. for 1 hr, 1 mol/Lhydrochloric acid (20 mL) was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=7:3→1:1) to givethe title compound as a pale-red oil (yield 330 mg, 95%).

¹H-NMR (CDCl₃) δ: 4.43 (2H, s), 6.06 (1H, d, J=5.5 Hz), 7.31-7.62 (10H,m).

Reference Example 189[2-Chloro-4-fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol

A solution (20 mL) of ethyl2-chloro-4-fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate(250 mg) in tetrahydrofuran was cooled to −70° C., and a 1.5 mol/Lsolution (6 mL) of diisobutylaluminum hydride in toluene was addeddropwise by small portions. The mixture was further stirred at −70° C.for 1 hr, 1 mol/L hydrochloric acid (50 mL) was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (eluent: hexane-ethyl acetate=7:3→1:1)to give the title compound as a colorless oil (yield 210 mg, 94%).

¹H-NMR (CDCl₃) δ: 4.49 (2H, s), 7.31-7.51 (7H, m), 7.60-7.68 (3H, m).

Reference Example 190[4-Fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol

A solution (10 mL) of ethyl4-fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (60 mg) intetrahydrofuran was cooled to −70° C., and a 1.5 mol/L solution (0.5 mL)of diisobutylaluminum hydride in toluene was added dropwise by smallportions. The mixture was further stirred at −70° C. for 1 hr, 1 mol/Lhydrochloric acid (20 mL) was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=7:3) to give thetitle compound as a colorless oil (yield 40 mg, 75%).

¹H-NMR (CDCl₃) δ: 4.60 (2H, br), 7.20-7.23 (2H, m), 7.31-7.56 (9H, m).

Reference Example 1912-Methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde

To a mixture of [2-methyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol(6.35 g), dimethyl sulfoxide (50 mL) and triethylamine (25 mL) was addedsulfur trioxide.pyridine complex (4.57 g), and the mixture was stirredat room temperature for 12 hr. Saturated aqueous sodiumhydrogencarbonate solution was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed withsaturated aqueous sodium hydrogencarbonate solution, water and saturatedbrine, dried over anhydrous sodium sulfate, filtered, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=2:1) to give a white titlecompound (yield 5.27 g, 84%).

¹H-NMR (CDCl₃) δ: 2.62 (3H, s), 6.65 (1H, d, J=3.6 Hz), 7.35 (1H, d,J=3.6 Hz), 7.55-7.61 (2H, m), 7.66-7.71 (1H, m), 7.85-7.88 (2H, m), 9.89(1H, s).

Reference Example 1925-Bromo-4-ethyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde

Using [5-bromo-4-ethyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol (1.05g), tetra-n-propylammonium perruthenate (54.3 mg), N-methylmorpholineN-oxide (543 mg) and molecular sieves 4A powder (522 mg), a procedure asin Reference Example 6 was performed to give the title compound as whitecrystals (yield 0.51 g, 49%).

¹H-NMR (CDCl₃) δ: 1.06 (3H, t, J=7.8 Hz), 2.62 (2H, q, J=7.8 Hz),7.55-7.63 (2H, m), 7.67-7.75 (1H, m), 7.96-8.00 (2H, m), 8.09 (1H, s),9.81 (1H, s).

Reference Example 1935-Bromo-1-{[3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrole-3-carbaldehyde

Using{5-bromo-1-{[3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrol-3-yl}methanol(4.88 g) and sulfur trioxide.pyridine complex (2.19 g), a procedure asin Reference Example 191 was performed to give the title compound as awhite solid (yield 2.80 g, 58%).

¹H-NMR (CDCl₃) δ: 3.12 (3H, s), 6.77 (1H, d, J=1.8 Hz), 7.86 (1H, t,J=7.8 Hz), 8.10 (1H, d, J=1.8 Hz), 8.26-8.30 (2H, m), 8.61-8.62 (1H, m),9.79 (1H, s).

Reference Example 1942-Chloro-5-phenyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrole-3-carbaldehyde

5-Phenyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrole-3-carbaldehyde(300 mg) was dissolved in N,N-dimethylformamide (6 mL),N-chlorosuccinimide (116 mg) was added at room temperature, and themixture was stirred for 24 hr. Water was added to the reaction mixture,and the mixture was extracted with ethyl acetate. The extract was washedwith 3% potassium hydrogensulfate solution and saturated brine, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=19:1→4:1) to give the title compound ascolorless crystals (yield 200 mg, 61%).

¹H-NMR (CDCl₃) δ: 6.55 (1H, s), 7.31-7.35 (2H, m), 7.38-7.50 (3H, m),7.74-7.80 (4H, m), 9.94 (1H, s).

Reference Example 1951-[(3-Chlorophenyl)sulfonyl]-2-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde

Using{1-[(3-chlorophenyl)sulfonyl]-2-methyl-5-phenyl-1H-pyrrol-3-yl}methanol(340 mg), tetra-n-propylammonium perruthenate (17.7 mg),N-methylmorpholine N-oxide (179 mg) and molecular sieves 4A powder (189mg), a procedure as in Reference Example 6 was performed to give thetitle compound as a brown oil (yield 237 mg, 70%).

¹H-NMR (CDCl₃) δ: 2.90 (3H, s), 6.50 (1H, s), 7.17-7.21 (2H, m),7.28-7.43 (6H, m), 7.51-7.55 (1H, m), 10.03 (1H, s).

Reference Example 1965-Phenyl-1-{[4-(trifluoromethoxyphenyl)sulfonyl]-1H-pyrrole-3-carbaldehyde

To a solution (15 mL) of(5-phenyl-1-{[4-(trifluoromethoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl)methanol(0.70 g) in acetonitrile were added tetra-n-propylammonium perruthenate(55 mg), N-methylmorpholine N-oxide (0.69 g) and molecular sieves 4Apowder (0.45 g), and the mixture was stirred at room temperature for 3hr. The reaction mixture was concentrated under reduced pressure, and tothe residue was added ethyl acetate and filtered through celite. Thefiltrate was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=3:1) to give the title compound as crystals (yield 0.42 g, 60%).

¹H-NMR (CDCl₃) δ: 6.59 (1H, s), 7.09-7.17 (4H, m), 7.27-7.44 (5H, m),8.12 (1H, d, J=1.9 Hz), 9.90 (1H, s).

Reference Example 1975-Phenyl-1-(2-thienylsulfonyl)-1H-pyrrole-3-carbaldehyde

To a solution (20 mL) of[5-phenyl-1-(2-thienylsulfonyl)-1H-pyrrol-3-yl]methanol (480 mg) inacetonitrile were added tetra-n-propylammonium perruthenate (80 mg),N-methylmorpholine N-oxide (407 mg) and molecular sieves 4A powder (500mg), and the mixture was stirred at room temperature for 1.5 hr. Thereaction mixture was diluted with ethyl acetate, filtered throughcelite, and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1→3:2) to give the title compound as colorlesscrystals (yield 272 mg, 57%).

¹H-NMR (CDCl₃) δ: 6.59 (1H, d, J=1.8 Hz), 6.90 (1H, dd, J=4.9 Hz, 3.9Hz), 7.05 (1H, dd, J=3.9 Hz, 1.4 Hz), 7.24-7.45 (5H, m), 7.62 (1H, dd,J=4.9 Hz, 1.4 Hz), 8.07 (1H, d, J=1.8 Hz), 9.88 (1H, s).

Reference Example 1982-Methyl-1-(phenylsulfonyl)-5-(3-thienyl)-1H-pyrrole-3-carbaldehyde

Using [2-methyl-1-(phenylsulfonyl)-5-(3-thienyl)-1H-pyrrol-3-yl]methanol(307 mg), tetra-n-propylammonium perruthenate (26.4 mg),N-methylmorpholine N-oxide (216 mg) and molecular sieves 4A powder (215mg), a procedure as in Reference Example 6 was performed to give thetitle compound as a brown oil (yield 309 g, 76%).

¹H-NMR (CDCl₃) δ: 2.90 (3H, s), 6.50 (1H, s), 7.02-7.06 (2H, m),7.23-7.26 (1H, m), 7.37-7.43 (4H, m), 7.54-7.60 (1H, m), 10.01 (1H, s).

Reference Example 1995-(4-Fluorophenyl)-2-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde

[5-(4-Fluorophenyl)-2-methyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol(1.08 g) was dissolved in acetonitrile (20 mL), tetra-n-propylammoniumperruthenate (100 mg), N-methylmorpholine N-oxide (0.52 g) and molecularsieves 4A powder (1.00 g) were added, and the mixture was stirred atroom temperature for 2 hr. The reaction mixture was concentrated underreduced pressure, and the residue was suspended in ethyl acetate andfiltered through celite. The filtrate was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=3:1) to give the titlecompound as colorless crystals (yield 0.71 g, 66%).

¹H-NMR (CDCl₃) δ: 2.89 (3H, s), 6.46 (1H, s), 6.99 (2H, t, J=8.7 Hz),7.11-7.21 (2H, m), 7.37-7.46 (4H, m), 7.56-7.62 (1H, m), 10.01 (1H, s).

Reference Example 2002,4-Dimethyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde

Using [2,4-dimethyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol(0.84 g), tetra-n-propylammonium perruthenate (57.3 mg),N-methylmorpholine N-oxide (437 mg) and molecular sieves 4A powder (422mg), a procedure as in Reference Example 6 was performed to give thetitle compound as a brown oil (yield 0.59 g, 71%).

¹H-NMR (CDCl₃) δ: 1.95 (3H, s), 2.88 (3H, s), 7.03-7.06 (2H, m),7.26-7.42 (7H, m), 7.54-7.60 (1H, m), 10.13 (1H, s).

Reference Example 2015-Phenyl-1-(phenylsulfonyl)-4-propyl-1H-pyrrole-3-carbaldehyde

Using [5-phenyl-1-(phenylsulfonyl)-4-propyl-1H-pyrrol-3-yl]methanol(2.73 g), tetra-n-propylammonium perruthenate (142 mg),N-methylmorpholine N-oxide (1.04 g) and molecular sieves 4A powder (1.5g), a procedure as in Reference Example 6 was performed to give thetitle compound as a pale-red oil (yield 1.33 g, 47%).

¹H-NMR (CDCl₃) δ: 0.72 (3H, t, J=7.5 Hz), 1.30-1.43 (2H, m), 2.31-2.37(2H, m), 6.94-6.97 (2H, m), 7.24-7.40 (7H, m), 7.52-7.58 (1H, m), 8.08(1H, s), 9.94 (1H, s).

Reference Example 2024,5-Diphenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde

Using [4,5-diphenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol (352 mg),tetra-n-propylammonium perruthenate (13.8 mg), N-methylmorpholineN-oxide (159 mg) and molecular sieves 4A powder (177 mg), a procedure asin Reference Example 6 was performed to give the title compound as whitecrystals (yield 250 mg, 72%).

¹H-NMR (CDCl₃) δ: 6.93-6.96 (2H, m), 7.04-7.09 (2H, m), 7.13-7.18 (5H,m), 7.26-7.35 (5H, m), 7.52-7.58 (1H, m), 8.25 (1H, s), 9.86 (1H, s).

Reference Example 2032-Chloro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde

To a solution (50 mL) of[2-chloro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol (830 mg)in acetonitrile were added tetra-n-propylammonium perruthenate (84 mg),N-methylmorpholine N-oxide (484 mg) and molecular sieves 4A powder (2.0g), and the mixture was stirred at room temperature for 5 hr. Thereaction mixture was diluted with ethyl acetate, filtered throughcelite, and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→4:1) to give the title compound as a colorlessoil (yield 440 mg, 53%).

¹H-NMR (CDCl₃) δ: 6.52 (1H, s), 7.32-7.52 (7H, m), 7.62-7.69 (3H, m),9.93 (1H, s).

Reference Example 2042-Fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde

To a solution (20 mL) of[2-fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol (330 mg)in acetonitrile were added tetra-n-propylammonium perruthenate (53 mg),N-methylmorpholine N-oxide (270 mg) and molecular sieves 4A powder (500mg), and the mixture was stirred at room temperature for 1.5 hr. Thereaction mixture was diluted with ethyl acetate, filtered throughcelite, and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→4:1) to give the title compound as a colorlessoil (yield 110 mg, 34%).

¹H-NMR (CDCl₃) δ: 6.32 (1H, d, J=5.1 Hz), 7.27-7.31 (2H, m), 7.35-7.52(5H, m), 7.62-7.69 (3H, m), 9.87 (1H, s).

Reference Example 2052-Chloro-4-fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde

To a solution (15 mL) of[2-chloro-4-fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol(210 mg) in acetonitrile were added tetra-n-propylammonium perruthenate(31 mg), N-methylmorpholine N-oxide (156 mg) and molecular sieves 4Apowder (500 mg), and the mixture was stirred at room temperature for 1.5hr. The reaction mixture was diluted with ethyl acetate, filteredthrough celite, and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=90:10→85:15) to give the title compound asa colorless oil (yield 140 mg, 67%).

¹H-NMR (CDCl₃) δ: 7.28-7.36 (2H, m), 7.42-7.55 (5H, m), 7.66-7.71 (3H,m), 9.92 (1H, s).

Reference Example 20614-Fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde

To a solution (10 mL) of[4-fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol (40 mg) inacetonitrile were added tetra-n-propylammonium perruthenate (21 mg),N-methylmorpholine N-oxide (82 mg) and molecular sieves 4A powder (1.0g), and the mixture was stirred at room temperature for 1.5 hr. Thereaction mixture was diluted with ethyl acetate, filtered throughcelite, and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=7:3) to give the title compound as a colorless oil(yield 10 mg, 25%).

¹H-NMR (CDCl₃) δ: 7.14-7.17 (2H, m), 7.33-7.61 (8H, m), 7.95 (1H, d,J=5.0 Hz), 9.91 (1H, s).

Reference Example 2075-Bromo-4-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde

Using methyl5-bromo-4-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate, aprocedure as in Reference Example 49 was performed to give the titlecompound as a colorless solid (1.78 g, yield 54%).

¹H-NMR (CDCl₃) δ: 2.14 (3H, s), 7.50-7.62 (3H, m), 7.91-7.96 (2H, m),8.04 (1H, s), 9.77 (1H, s).

Reference Example 208 4-Methyl-5-phenyl-1H-pyrrole-3-carbaldehyde

A suspension of5-bromo-4-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (1.78 g),phenylboronic acid (1.37 g), dichloro[bis(triphenylphosphine)]palladium(0.19 g) and sodium carbonate (1.72 g) in 1,2-dimethoxyethane (30mL)-water (10 mL) was stirred at 100° C. for 1 hr. 8 mol/L aqueoussodium hydroxide solution (15 mL) was added, and the mixture was stirredat 90° C. for 3 hr. After cooling, the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→1:1), and the obtained solid was washed withhexane to give the title compound as a pale-yellow solid (yield 815 mg,69%).

¹H-NMR (CDCl₃) δ: 2.47 (3H, s), 7.34-7.48 (6H, m), 8.58 (1H, br), 9.91(1H, s).

Reference Example 209 5-Bromo-1H-pyrrole-3-carbaldehyde

To a solution methyl5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate (4.16 g) intetrahydrofuran (40 mL) was added a 1.5 mol/L solution (26 mL) ofdiisobutylaluminum hydride in toluene at −78° C. and the mixture wasstirred at 0° C. for 30 min. Water (100 mL) was added to the reactionmixture, and the mixture was further stirred at 0° C. for 1 hr, and themixture was extracted with ethyl acetate. The extract was washed withwater and saturated brine, dried over anhydrous sodium sulfate,filtrated, and concentrated under reduced pressure. To a mixture of theresidue, dimethyl sulfoxide (25 mL) and triethylamine (13 mL) was addedsulfur trioxide.pyridine complex (2.20 g), and the mixture was stirredfor 1 hr. Water (100 mL) was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed withsaturated aqueous sodium hydrogencarbonate solution, water and saturatedbrine, dried over anhydrous sodium sulfate. The mixture was filtrated,and the filtrate was concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluent: hexane-ethylacetate=1:1) to give the title compound as a white solid (yield 1.24 g,59%).

¹H-NMR (CDCl₃) δ: 6.65-6.67 (1H, m), 7.38-7.40 (1H, m), 8.80 (1H, brs),9.71 (1H, s).

Reference Example 2102-Methyl-1-[(3-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde

A solution (10 mL) of ethyl2-methyl-1-[(3-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate(588 mg) in tetrahydrofuran was cooled to −78° C., a 1.5 mol/L toluenesolution (3.00 mL) of diisobutylaluminum hydride was added dropwise.After completion of the dropwise addition, the mixture was stirred at−78° C. for 30 min, and at room temperature for 30 min. 1 mol/lHydrochloric acid (10 mL) was added to the reaction mixture andextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. A solution (10 mL) of the residue in acetonitrile wascooled to 0° C., tetra-n-propylammonium perruthenate (53 mg),N-methylmorpholine N-oxide (358 mg) and molecular sieves 4A powder (1.0g) were added, and the mixture was stirred at room temperature for 2.5hr. The reaction mixture was concentrated under reduced pressure, andthe residue was suspended in ethyl acetate (30 mL) and filtered throughcelite. The filtrate was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→2:1) to give the title compound as apale-yellow oil (yield 250 mg, 48%).

¹H-NMR (CDCl₃) δ: 2.30 (3H, s), 2.89 (3H, s), 6.47 (1H, s), 7.10-7.40(9H, m), 10.01 (1H, s).

Reference Example 2111-[(2-Methyl-5-pyrimidine)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde

Under a nitrogen atmosphere, a solution of ethyl1-[(2-methyl-5-pyrimidine)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate(280 mg) in tetrahydrofuran (20 mL) was cooled to −78° C., a 1.5 mol/Lsolution (3.0 mL) of diisobutylaluminum in toluene was added whilestirring. After stirring at the same temperature for 15 min, the mixturewas allowed to warm to −40° C. over 30 min. Water (50 mL) was added, andafter stirring at the same temperature for 5 min, the mixture wasallowed to warm to 0° C. over 10 min. Ethyl acetate (30 mL) was added,and after stirring at the same temperature for 15 min, the mixture wasstirred at room temperature for 20 min. A gel-like mixture was filteredthrough celite, and celite was washed with ethyl acetate. The organiclayer was separated from the filtrate, washed with saturated brine,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was dissolved in tetrahydrofuran (50 mL),manganese dioxide (75% chemically treated product, 3.0 g) was added, andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was filtered through celite, and celite was washed with ethylacetate. The filtrate was concentrated under reduced pressure and theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→1:1) to give the title compound as apale-yellow solid (yield 150 mg, 61%).

¹H-NMR (CDCl₃) δ: 2.78 (3H, s), 6.64 (1H, s), 7.21-7.26 (2H, m),7.36-7.51 (3H, m), 8.10 (1H, s), 8.40 (2H, s), 9.90 (1H, s).

Reference Example 2124-Methyl-1-[(3-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde

Under a nitrogen atmosphere, a solution (60 mL) of ethyl4-methyl-1-[(3-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate(2.48 g) in tetrahydrofuran was cooled to −78° C., and a 1.5 mol/Lsolution (13 mL) of diisobutylaluminum hydride in toluene was addeddropwise over 15 min, and the mixture was further stirred at −78° C. for30 min. 1 mol/L Hydrochloric acid (60 mL) was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas washed with water and saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas dissolved in acetonitrile solution (100 mL), tetra-n-propylammoniumperruthenate (0.21 g), N-methylmorpholine N-oxide hydrate (1.31 g) andmolecular sieves 4A powder (6.0 g) were added, and the mixture wasstirred at room temperature for 2 hr. The reaction mixture wasconcentrated under reduced pressure, ethyl acetate (300 mL) was added tothe residue, the suspension was filtered through celite, and celite waswashed with ethyl acetate. The filtrate was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=19:1→3:1) to give the titlecompound as a yellow oil (yield 1.76 g, 80%).

¹H-NMR (CDCl₃) δ: 2.02 (3H, s), 2.25 (3H, s), 6.99-7.43 (9H, m), 8.05(1H, s), 9.96 (1H, s).

Reference Example 2131-[(4-Fluorophenyl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde

Under a nitrogen atmosphere, a solution (40 mL) of methyl1-[(4-fluorophenyl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carboxylate(1.48 g) in tetrahydrofuran was cooled to −78° C., and a 1.5 mol/Lsolution (7.9 mL) of diisobutylaluminum hydride in toluene was addeddropwise over 15 min, and the mixture was further stirred at −78° C. for30 min. 1 mol/L Hydrochloric acid (40 mL) was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas washed with water and saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas dissolved in acetonitrile solution (60 mL), addedtetra-n-propylammonium perruthenate (0.14 g), N-methylmorpholine N-oxidehydrate (0.80 g) and molecular sieves 4A powder (4.0 g), and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasconcentrated under reduced pressure, ethyl acetate (200 mL) was added tothe residue, the suspension was filtered through celite, and celite waswashed with ethyl acetate. The filtrate was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=19:1→3:1) to give the titlecompound as a colorless oil (yield 721 mg, 53%).

¹H-NMR (CDCl₃) δ: 2.03 (3H, s), 6.96-7.04 (4H, m), 7.26-7.42 (5H, m),8.04 (1H, s), 9.96 (1H, s).

Reference Example 2142-Methyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

A solution (15 mL) of ethyl2-methyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxylate (980mg) in tetrahydrofuran was cooled to −78° C., a 1.5 mol/L solution (5.3mL) of diisobutylaluminum hydride in toluene was added dropwise over 10min, and the mixture was warmed to 0° C. over 2 hr. Water (100 mL) andethyl acetate (20 mL) were added, and the mixture was stirred at roomtemperature for 30 min. The reaction mixture was filtered throughcelite, and the organic layer was separated, washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was dissolved in acetonitrile solution (25mL), tetra-n-propylammonium perruthenate (93 mg), N-methylmorpholineN-oxide hydrate (466 mg) and molecular sieves 4A powder (500 mg) wereadded, and the mixture was stirred at room temperature for 2 hr. Thereaction mixture was concentrated under reduced pressure, and ethylacetate (30 mL) was added to the residue. The mixture was filteredthrough celite, and celite was washed with ethyl acetate. The filtratewas concentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent: hexane-ethyl acetate=19:1→1:1)to give the title compound as a yellow oil (yield 235 mg, 27%).

¹H-NMR (CDCl₃) δ: 2.93 (3H, s), 6.51 (1H, s), 7.18-7.42 (6H, m),7.59-7.64 (1H, m), 8.60 (1H, s), 8.77-8.79 (1H, m), 10.03 (1H, s).

Reference Example 2154-Chloro-2-methyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde

Using ethyl4-chloro-2-methyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate(610 mg), a 1.5 mol/L solution (6.0 mL) of diisobutylaluminum hydride intoluene, tetra-n-propylammonium perruthenate (53 mg), N-methylmorpholineN-oxide (195 mg) and molecular sieves 4A powder (300 mg), a procedure asin Reference Example 49 was performed to give the title compound as apale-yellow solid (yield 301 mg, 55%).

¹H-NMR (CDCl₃) δ: 2.94 (3H, s), 7.13-7.16 (2H, m), 7.33-7.46 (7H, m),7.57-7.62 (1H, m), 10.1 (1H, s).

Reference Example 2165-Butyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde

Using ethyl 5-butyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (780mg), a procedure as in Reference Example 212 was performed to give thetitle compound as a colorless solid (yield 553 mg, 82%).

¹H-NMR (CDCl₃) δ: 0.84-0.89 (3H, m), 1.26-1.50 (2H, m), 1.48-1.57 (2H,m), 2.59-2.65 (2H, m), 6.43 (1H, m), 7.55-7.60 (2H, m), 7.66-7.71 (1H,m), 7.82-7.84 (2H, m), 7.95 (1H, s), 9.81 (1H, s).

Reference Example 2175-Cyclohexyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde

Using ethyl 5-cyclohexyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate(640 mg), a procedure as in Reference Example 212 was performed to givethe title compound as a solid (yield 424 mg, 75%).

¹H-NMR (CDCl₃) δ: 1.14-1.28 (6H, m), 1.60-1.72 (4H, m), 2.82 (1H, m),6.44 (1H, s), 7.54-7.59 (2H, m), 7.64-7.67 (1H, m), 7.80-7.83 (2H, m),7.91 (1H, s), 9.81 (1H, s).

Reference Example 2185-Cyclopropyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde

Using methyl 5-cyclopropyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate(406 mg), a procedure as in Reference Example 212 was performed to givethe title compound as an oil (yield 247 mg, 68%).

¹H-NMR (CDCl₃) δ: 0.32-0.38 (2H, m), 0.73-0.79 (2H, m), 2.01-2.06 (1H,m), 6.24 (1H, s), 7.54-7.59 (2H, m), 7.66-7.71 (1H, m), 7.88-7.90 (2H,m), 7.96 (1H, s), 9.79 (1H, s).

Reference Example 2191-{[3-(Methylsulfonyl)phenyl]sulfonyl}-5-phenyl-1H-pyrrole-3-carbaldehyde

To a solution (10 mL) of 5-phenyl-1H-pyrrole-3-carbaldehyde (100 mg) intetrahydrofuran was added sodium hydride (60% in oil, 47 mg) at roomtemperature and the mixture was stirred for 30 min. 15-Crown-5 (257 mg)was added dropwise and the mixture was stirred for 30 min,[3-(methylsulfonyl)benzene]sulfonyl chloride (223 mg) was added, and themixture was further stirred for 15 hr. Saturated brine was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=7:3→1:1) to give the title compound as a pale-yellow oil (yield160 mg, 70%).

¹H-NMR (CDCl₃) δ: 2.98 (3H, s), 6.61 (1H, d, J=1.8 Hz), 7.16-7.20 (2H,m), 7.30-7.36 (2H, m), 7.41-7.47 (1H, m), 7.57-7.59 (2H, m), 7.92-7.94(1H, m), 8.10-8.13 (2H, m), 9.90 (1H, s).

Reference Example 2201-{[3-(Ethylsulfonyl)phenyl]sulfonyl}-5-phenyl-1H-pyrrole-3-carbaldehyde

Using 5-phenyl-1H-pyrrole-3-carbaldehyde (171 mg), sodium hydride (60%in oil, 58 mg), 15-crown-5 (264 mg) and[3-(ethylsulfonyl)benzene]sulfonyl chloride (322 mg), a procedure as inReference Example 219 was performed to give the title compound as apale-yellow oil (yield 348 mg, 86%).

¹H-NMR (CDCl₃) δ: 1.23 (3H, t, J=7.5 Hz), 3.03 (2H, q, J=7.5 Hz), 6.61(1H, d, J=2.1 Hz), 7.15-7.18 (2H, m), 7.30-7.36 (2H, m), 7.41-7.44 (1H,m), 7.55-7.57 (2H, m), 7.91-7.92 (1H, m), 8.05-8.09 (1H, m), 8.13 (1H,d, J=2.1 Hz), 9.91 (1H, s).

Reference Example 2211-(2,3-Dihydro-1,4-benzodioxin-6-ylsulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde

Using 5-phenyl-1H-pyrrole-3-carbaldehyde (171 mg), sodium hydride (60%in oil, 72 mg), 15-crown-5 (330 mg) and2,3-dihydro-1,4-benzodioxine-6-sulfonyl chloride (352 mg), a procedureas in Reference Example 219 was performed to give the title compound asa pale-yellow oil (yield 258 mg, 70%).

¹H-NMR (CDCl₃) δ: 4.22-4.30 (4H, m), 6.56 (1H, d, J=2.1 Hz), 6.71-6.85(3H, m), 7.18-7.22 (2H, m), 7.30-7.44 (3H, m), 8.06 (1H, d, J=2.1 Hz),9.87 (1H, s).

Reference Example 2222-[(4-Formyl-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzonitrile

Using 5-phenyl-1H-pyrrole-3-carbaldehyde (171 mg), sodium hydride (60%in oil, 72 mg), 15-crown-5 (330 mg) and (2-cyanobenzene)sulfonylchloride (302 mg), a procedure as in Reference Example 219 was performedto give the title compound as a pale-yellow oil (yield 253 mg, 75%).

¹H-NMR (CDCl₃) δ: 6.62 (1H, d, J=1.8 Hz), 7.04-7.09 (2H, m), 7.18-7.26(3H, m), 7.32-7.42 (2H, m), 7.60-7.68 (1H, m), 7.75-7.79 (1H, m), 8.35(1H, d, J=1.8 Hz), 9.93 (1H, s).

Reference Example 2234-[(4-Formyl-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzonitrile

Using 5-phenyl-1H-pyrrole-3-carbaldehyde (171 mg), sodium hydride (60%in oil, 72 mg), 15-crown-5 (330 mg) and (4-cyanobenzene)sulfonylchloride (302 mg), a procedure as in Reference Example 219 was performedto give the title compound as a pale-yellow oil (yield 303 mg, 90%).

¹H-NMR (CDCl₃) δ: 6.60 (1H, d, J=2.1 Hz), 7.13-7.16 (2H, m), 7.30-7.46(5H, m), 7.58-7.62 (2H, m), 8.10 (1H, d, J=2.1 Hz), 9.90 (1H, s).

Reference Example 224 Methyl2-[(4-formyl-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoate

Using 5-phenyl-1H-pyrrole-3-carbaldehyde (513 mg), sodium hydride (60%in oil, 216 mg), 15-crown-5 (990 mg) and methyl2-(chlorosulfonyl)benzoate (1.06 g), a procedure as in Reference Example219 was performed to give the title compound as a pale-yellow oil (yield664 mg, 60%).

¹H-NMR (CDCl₃) δ: 3.88 (3H, s), 6.59 (1H, d, J=1.8 Hz), 7.07 (1H, d,J=7.2 Hz), 7.14-7.26 (5H, m), 7.33-7.36 (1H, m), 7.56-7.58 (2H, m), 8.11(1H, d, J=1.8 Hz), 9.92 (1H, s).

Reference Example 225 Methyl3-[(4-formyl-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoate

Using 5-phenyl-1H-pyrrole-3-carbaldehyde (1.32 g), sodium hydride (60%in oil, 444 mg), 15-crown-5 (2.04 g) and methyl3-(chlorosulfonyl)benzoate (2.17 g), a procedure as in Reference Example219 was performed to give the title compound as a pale-yellow oil (yield1.96 g, 69%).

¹H-NMR (CDCl₃) δ: 3.92 (3H, s), 6.57 (1H, d, J=2.1 Hz), 7.12-7.15 (2H,m), 7.26-7.32 (2H, m), 7.37-7.49 (3H, m), 7.96-7.97 (1H, m), 8.13-8.14(1H, m), 8.18-8.22 (1H, m), 9.90 (1H, s).

Reference Example 2262-Fluoro-4-[(4-formyl-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzonitrile

Using 5-phenyl-1H-pyrrole-3-carbaldehyde (172 mg), sodium hydride (60%in oil, 61.4 mg), 15-crown-5 (0.30 mL) and(4-cyano-3-fluorobenzene)sulfonyl chloride (433 mg), a procedure as inReference Example 219 was performed to give the title compound as whitecrystals (yield 283 mg, 79%).

¹H-NMR (CDCl₃) δ: 6.35 (d, 1H, J=1.8 Hz), 7.06-7.09 (1H, m), 7.16-7.25(3H, m), 7.34-7.39 (2H, m), 7.45-7.50 (1H, m), 7.60-7.64 (1H, m), 8.08(1H, d, J=1.8 Hz), 9.91 (1H, s).

Reference Example 2272-Chloro-4-[(4-formyl-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzonitrile

Using 5-phenyl-1H-pyrrole-3-carbaldehyde (175 mg), sodium hydride (60%in oil, 63.6 mg), 15-crown-5 (0.31 mL) and(3-chloro-4-cyanobenzene)sulfonyl chloride (675 mg), a procedure as inReference Example 219 was performed to give the title compound as whitecrystals (yield 310 mg, 82%).

¹H-NMR (CDCl₃) δ: 6.63 (1H, d, J=1.8 Hz), 7.16-7.20 (2H, m), 7.30-7.40(4H, m), 7.46-7.52 (1H, m), 7.63-7.66 (1H, m), 8.08 (1H, d, J=1.8 Hz),9.91 (1H, s).

Reference Example 2281-[(1,1-Dioxido-2,3-dihydro-1-benzothien-6-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde

Using 5-phenyl-1H-pyrrole-3-carbaldehyde (172 mg), sodium hydride (60%in oil, 61.6 mg), 15-crown-5 (0.30 mL) and6-(2,3-dihydro-1-benzothiophene)sulfonyl chloride 1,1-dioxide (394 mg),a procedure as in Reference Example 219 was performed to give the titlecompound as white crystals (yield 116 mg, 29%).

¹H-NMR (CDCl₃) δ: 3.39-3.44 (2H, m), 3.50-3.55 (2H, m), 6.60 (1H, d,J=1.8 Hz), 7.17-7.20 (2H, m), 7.34-7.39 (3H, m), 7.45-7.54 (2H, m), 7.62(1H, d, J=2.1 Hz), 8.09 (1H, d, J=1.8 Hz), 9.89 (1H, s).

Reference Example 2291-(1,3-Benzothiazol-6-ylsulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde

Using 5-phenyl-1H-pyrrole-3-carbaldehyde (135 mg), sodium hydride (60%in oil, 38.3 mg), 15-crown-5 (0.18 mL) and 6-benzothiazolesulfonylchloride (206 mg), a procedure as in Reference Example 219 was performedto give the title compound as white crystal (yield 248 mg, 85%).

¹H-NMR (CDCl₃) δ: 6.56 (1H, d, J=1.8 Hz), 7.08-7.11 (2H, m), 7.23-7.28(2H, m), 7.38-7.43 (1H, m), 7.49-7.52 (1H, m), 7.80 (1H, d, J=1.8 Hz),8.08 (1H, d, J=9.0 Hz), 8.17 (1H, d, J=1.8 Hz), 9.23 (1H, s), 9.90 (1H,s).

Reference Example 2301-(1-Benzothien-2-ylsulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde

To a solution (10 mL) of 5-phenyl-1H-pyrrole-3-carbaldehyde (100 mg) intetrahydrofuran was added sodium hydride (60% in oil, 47 mg) at roomtemperature and the mixture was stirred for 30 min. 15-Crown-5 (257 mg)was added dropwise and the mixture was stirred for 30 min,2-benzothiophenesulfonyl chloride (204 mg) was added, and the mixturewas further stirred for 1 hr. Saturated brine was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (eluent: hexane-ethyl acetate=4:1→3:2)to give the title compound as a colorless oil (yield 180 mg, 84%).

¹H-NMR (CDCl₃) δ: 6.59 (1H, d, J=1.8 Hz), 7.18-7.32 (5H, m), 7.40-7.54(3H, m), 7.67-7.80 (2H, m), 8.10 (1H, d, J=1.8 Hz), 9.89 (1H, s).

Reference Example 2311-{[4-(Methylsulfonyl)phenyl]sulfonyl}-5-phenyl-1H-pyrrole-3-carbaldehyde

To a solution (14 mL) of 5-phenyl-1H-pyrrole-3-carbaldehyde (140 mg) intetrahydrofuran was added sodium hydride (60% in oil, 66 mg) at roomtemperature and the mixture was stirred for 30 min. 15-Crown-5 (361 mg)was added dropwise and the mixture was stirred for 30 min,[4-(methylsulfonyl)benzene]sulfonyl chloride (313 mg) was added, and themixture was further stirred for 1 hr. Saturated brine was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=7:3→1:1), crystallized from ethyl acetate-diisopropyl ethermixed solvent (1:1) to give the title compound as yellow crystals (yield67 mg, 21%).

¹H-NMR (CDCl₃) δ: 3.05 (3H, s), 6.61 (1H, d, J=1.8 Hz), 7.14-7.17 (2H,m), 7.30-7.35 (2H, m), 7.41-7.52 (3H, m), 7.87-7.91 (2H, m), 8.12 (1H,d, J=1.8 Hz), 9.90 (1H, s).

Reference Example 2321-[(3-Acetylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde

To a solution (20 mL) of 5-phenyl-1H-pyrrole-3-carbaldehyde (200 mg) intetrahydrofuran was added sodium hydride (60% in oil, 94 mg) at roomtemperature and the mixture was stirred for 30 min. 15-Crown-5 (514 mg)was added dropwise and the mixture was stirred for 30 min,(3-acetylbenzene)sulfonyl chloride (384 mg) was added, and the mixturewas further stirred for 2 hr. Saturated brine was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (eluent: hexane-ethyl acetate=7:3) togive the title compound as a yellow oil (yield 200 mg, 48%).

¹H-NMR (CDCl₃) δ: 2.46 (3H, s), 6.58 (1H, d, J=1.8 Hz), 7.14-7.17 (2H,m), 7.26-7.33 (2H, m), 7.38-7.56 (3H, m), 7.78-7.78 (1H, m), 8.11-8.14(2H, m), 9.90 (1H, s).

Reference Example 2331-[(3-Nitrophenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde

To a solution (40 mL) of 5-phenyl-1H-pyrrole-3-carbaldehyde (520 mg) intetrahydrofuran was added sodium hydride (60% in oil, 364 mg) at roomtemperature and the mixture was stirred for 30 min. 15-Crown-5 (2.0 g)was added dropwise and the mixture was stirred for 30 min,(3-nitrobenzene)sulfonyl chloride (1.35 g) was added, and the mixturewas further stirred for 1 hr. Saturated brine was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (eluent: hexane-ethyl acetate=4:1→2:3),crystallized from diisopropyl ether to give the title compound aspale-yellow crystals (yield 810 mg, 75%).

¹H-NMR (CDCl₃) δ: 6.61 (1H, d, J=1.8 Hz), 7.13-7.16 (2H, m), 7.29-7.34(2H, m), 7.40-7.46 (1H, m), 7.55-7.60 (1H, m), 7.64-7.68 (1H, m),8.06-8.07 (1H, m), 8.13 (1H, d, J=1.8 Hz), 8.37-8.41 (1H, m), 9.91 (1H,s).

Reference Example 2345-Phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

Under an argon atmosphere, 5-phenyl-1H-pyrrole-3-carbaldehyde (342 mg)was dissolved in absolute tetrahydrofuran (20 mL) and sodium hydride(60% in oil, 240 mg) was added while stirring at room temperature. Afterstirring at the same temperature for 15 min, 15-crown-5 (1.21 mL) wasadded, and the mixture was further stirred at the same temperature for15 min. Pyridin-3-ylsulfonyl chloride hydrochloride (642 mg) was added,and the mixture was further stirred at the same temperature for 30 min.The reaction mixture was diluted with ethyl acetate, washed successivelywith saturated aqueous sodium hydrogencarbonate solution and saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=19:1→1:1) togive the title compound as a brown solid (yield 470 mg, 75%).

¹H-NMR (CDCl₃) δ: 6.60 (1H, d, J=1.8 Hz), 7.15-7.19 (2H, m), 7.25-7.37(3H, m), 7.42-7.48 (1H, m), 7.53-7.57 (1H, m), 8.13 (1H, d, J=1.8 Hz),8.49-8.50 (1H, m), 8.74-8.76 (1H, m), 9.90 (1H, s).

Reference Example 2351-[(6-Methoxypyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde

Under an argon atmosphere, 5-phenyl-1H-pyrrole-3-carbaldehyde (171 mg)was dissolved in absolute tetrahydrofuran (20 mL), and sodium hydride(60% in oil, 200 mg) was added at room temperature while stirring. Afterstirring at the same temperature for 15 min, 15-crown-5 (1.01 mL) wasadded, and the mixture was further stirred at the same temperature for15 min. 6-Methoxypyridin-3-ylsulfonyl chloride (623 mg) was added, andthe mixture was stirred at the same temperature for 1 hr. The reactionmixture was diluted with ethyl acetate, washed successively withsaturated aqueous sodium hydrogencarbonate solution and saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure and the residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=19:1→1:1) to give the titlecompound as an oil (yield 59 mg, 17%).

¹H-NMR (CDCl₃) δ: 3.95 (3H, s), 6.59-6.62 (2H, m), 7.19-7.44 (6H, m),8.08-8.10 (2H, m), 9.88 (1H, s).

Reference Example 2361-(6-Chloropyridin-3-ylsulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde

Under an argon atmosphere, 5-phenyl-1H-pyrrole-3-carbaldehyde (514 mg)was dissolved in absolute tetrahydrofuran (15 mL), and sodium hydride(60% in oil, 180 mg) was added at room temperature while stirring. Afterstirring at the same temperature for 15 min, 15-crown-5 (0.90 mL) wasadded, and the mixture was further stirred at the same temperature for15 min. 6-Chloropyridin-3-ylsulfonyl chloride (827 mg) was added, andthe mixture was further stirred at the same temperature for 1 hr. Thereaction mixture was diluted with ethyl acetate, washed successivelywith saturated aqueous sodium hydrogencarbonate solution and saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=19:1→7:3) togive the title compound as an oil (yield 762 mg, 73%).

¹H-NMR (CDCl₃) δ: 6.62 (1H, s), 7.19-7.49 (7H, m), 8.09 (1H, s),8.24-8.26 (1H, m), 8.90 (1H, s).

Reference Example 2371-(2-Chloropyridin-3-ylsulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde

By a reaction under similar conditions as in Reference 5 Example 234 andusing 5-phenyl-1H-pyrrole-3-carbaldehyde (514 mg), sodium hydride (60%in oil, 180 mg), 15-crown-5 (0.90 mL) and 2-chloro-3-pyridinesulfonylchloride (716 mg), the title compound was obtained as an amorphous form(yield 716 mg, 69%).

¹H-NMR (CDCl₃) δ: 6.64 (1H, s), 6.70-6.90 (1H, m), 7.05-7.08 (2H, m),7.15-7.18 (2H, m), 7.26-7.32 (1H, m), 7.55-7.59 (1H, m), 8.26 (1H, s),8.44-8.46 (1H, m), 9.94 (1H, s).

Reference Example 2381-(2-Chloropyrimidin-5-ylsulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde

By a reaction under similar conditions as in Reference Example 234 andusing 5-phenyl-1H-pyrrole-3-carbaldehyde (342 mg), sodium hydride (60%in oil, 120 mg), 15-crown-5 (0.60 mL) and 2-chloro-5-pyrimidinesulfonylchloride (554 mg), the title compound was obtained as a yellow solid(yield 390 mg, 56%).

¹H-NMR (CDCl₃) δ: 6.68 (1H, s), 7.22-7.26 (2H, m), 7.39-7.52 (3H, m),8.09 (1H, s), 8.35 (2H, s), 9.91 (1H, s).

Reference Example 2391-[(6-Chloro-5-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde

By a reaction under similar conditions as in Reference Example 234 andusing 5-phenyl-1H-pyrrole-3-carbaldehyde (171 mg), sodium hydride (60%in oil, 60 mg), 15-crown-5 (0.30 mL) and6-chloro-5-methylpyridine-3-sulfonyl chloride (270 mg), the titlecompound was obtained as a solid (yield 244 mg, 68%).

¹H-NMR (CDCl₃) δ: 2.27 (3H, s), 6.62 (1H, s), 7.20-7.26 (3H, m),7.35-7.49 (3H, m), 8.09 (1H, s), 8.13 (1H, m), 9.90 (1H, s).

Reference Example 2405-(2-Fluorophenyl)-1-{[3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrole-3-carbaldehyde

To a solution (48 mL) of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde(475 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 302mg) at room temperature and the mixture was stirred for 30 min.15-Crown-5 (1.66 g) was added dropwise and the mixture was stirred for30 min, [3-(methylsulfonyl)benzene]sulfonyl chloride (1.28 g) was added,and the mixture was further stirred for 15 hr. Saturated brine was addedto the reaction mixture, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=7:3→2:3), and crystallized from diisopropylether.ethyl acetate mixed solvent (4:1) to give the title compound ascolorless crystals (yield 576 mg, 56%).

¹H-NMR (CDCl₃) δ: 3.03 (3H, s), 6.69 (1H, d, J=1.8 Hz), 6.97-7.02 (1H,m), 7.19-7.22 (2H, m), 7.43-7.50 (1H, m), 7.63-7.75 (2H, m), 7.99-8.00(1H, m), 8.14 (1H, d, J=1.8 Hz), 8.16-8.19 (1H, m), 9.91 (1H, s).

Reference Example 2411-{[3-(Ethylsulfonyl)phenyl]sulfonyl}-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde

Using 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (147 mg), sodiumhydride (60% in oil, 45 mg), 15-crown-5 (205 mg) and[3-(ethylsulfonyl)benzene]sulfonyl chloride (250 mg), a procedure as inReference Example 219 was performed to give the title compound as apale-yellow oil (yield 181 mg, 55%).

¹H-NMR (CDCl₃) δ: 1.25 (3H, t, J=7.5 Hz), 3.08 (2H, q, J=7.5 Hz), 6.68(1H, d, J=2.4 Hz), 6.95-7.02 (1H, m), 7.18-7.21 (2H, m), 7.43-7.50 (1H,m), 7.62-7.72 (2H, m), 7.16-7.97 (1H, m), 8.12-8.15 (2H, m), 9.91 (1H,s).

Reference Example 2422-{[2-(2-Fluorophenyl)-4-formyl-1H-pyrrol-1-yl]sulfonyl}benzonitrile

To a solution (28 mL) of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde(284 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 181mg) at room temperature and the mixture was stirred for 30 min.15-Crown-5 (992 mg) was added dropwise and the mixture was stirred for30 min, (2-cyanobenzene)sulfonyl chloride (606 mg) was added, and themixture was further stirred for 1 hr. Saturated brine was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=4:1→2:3) to give the title compound as colorless crystals (yield410 mg, 77%).

¹H-NMR (CDCl₃) δ: 6.70 (1H, d, J=1.7 Hz), 6.83-6.89 (1H, m), 7.08-7.18(2H, m), 7.32-7.52 (3H, m), 7.70-7.75 (1H, m), 7.82-7.85 (1H, m), 8.39(1H, d, J=1.7 Hz), 9.94 (1H, s).

Reference Example 2434-{[2-(2-Fluorophenyl)-4-formyl-1H-pyrrol-1-yl]sulfonyl}benzonitrile

To a solution (28 mL) of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde(284 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 181mg) at room temperature and the mixture was stirred for 30 min.15-Crown-5 (992 mg) was added dropwise and the mixture was stirred for30 min, (4-cyanobenzene)sulfonyl chloride (606 mg) was added, and themixture was further stirred for 1 hr. Saturated brine was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=4:1→2:3) to give the title compound as colorless crystals (yield420 mg, 79%).

¹H-NMR (CDCl₃) δ: 6.69 (1H, d, J=1.8 Hz), 6.98-7.04 (1H, m), 7.16-7.18(2H, m), 7.42-7.49 (1H, m), 7.51-7.54 (2H, m), 7.67-7.71 (2H, m), 8.12(1H, d, J=1.8 Hz), 9.90 (1H, s).

Reference Example 2445-(2-Fluorophenyl)-1-[(2-fluorophenyl)sulfonyl]-1H-pyrrole-3-carbaldehyde

To a solution (25 mL) of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde(250 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 106mg) at room temperature and the mixture was stirred for 30 min.15-Crown-5 (583 mg) was added dropwise and the mixture was stirred for30 min, (2-fluorobenzene)sulfonyl chloride (386 mg) was added, and themixture was further stirred for 1 hr. Saturated brine was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=4:1→3:2) to give the title compound as colorless crystals (yield360 mg, 78%).

¹H-NMR (CDCl₃) δ: 6.67 (1H, d, J=1.8 Hz), 6.86-6.92 (1H, m), 7.03-7.23(5H, m), 7.33-7.41 (1H, m), 7.59-7.66 (1H, m), 8.21-8.22 (1H, m), 9.91(1H, s).

Reference Example 2455-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

To a solution (96 mL) of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde(475 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 503mg) at room temperature and the mixture was stirred for 30 min.15-Crown-5 (2.77 g) was added dropwise and the mixture was stirred for30 min, pyridine-3-sulfonyl chloride hydrochloride (1.35 g) was added,and the mixture was further stirred for 3 hr. Saturated brine was addedto the reaction mixture, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=7:3→2:3), and crystallized from diisopropylether-ethyl acetate (4:1) to give the title compound as colorlesscrystals (yield 680 mg, 82%).

¹H-NMR (CDCl₃) δ: 6.68 (1H, d, J=1.8 Hz), 6.99-7.05 (1H, m), 7.16-7.19(2H, m), 7.35-7.39 (1H, m), 7.45-7.51 (1H, m), 7.69-7.73 (1H, m), 8.14(1H, d, J=1.8 Hz), 8.58-8.59 (1H, m), 8.81-8.83 (1H, m), 9.91 (1H, s).

Reference Example 2461-{[3-(Methylsulfonyl)phenyl]sulfonyl}-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbaldehyde

To a solution (24 mL) of5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbaldehyde (240 mg) intetrahydrofuran was added sodium hydride (60% in oil, 121 mg) at roomtemperature and the mixture was stirred for 30 min. 15-Crown-5 (663 mg)was added dropwise and the mixture was stirred for 30 min,[3-(methylsulfonyl)benzene]sulfonyl chloride (512 mg) was added, and themixture was further stirred for 2 hr. Saturated brine was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=7:3→1:1) to give the title compound as colorless crystals (yield340 mg, 74%).

¹H-NMR (CDCl₃) δ: 3.00 (3H, s), 6.68-6.68 (1H, m), 7.46-7.48 (1H, m),7.59-7.70 (5H, m), 7.94-7.94 (1H, m), 8.14-8.18 (2H, m), 9.92 (1H, s)

Reference Example 2471-(Pyridin-3-ylsulfonyl)-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbaldehyde

To a solution (36 mL) of5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbaldehyde (240 mg) intetrahydrofuran was added sodium hydride (60% in oil, 201 mg) at roomtemperature and the mixture was stirred for 30 min. 15-Crown-5 (1.11 g)was added dropwise and the mixture was stirred for 30 min.Pyridine-3-sulfonyl chloride hydrochloride (537 mg) was added, and themixture was further stirred for 3 hr. Saturated brine was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=4:1→2:3) and crystallized from diisopropyl ether to give thetitle compound as colorless crystals (yield 380 mg, about 100%).

¹H-NMR (CDCl₃) δ: 6.69 (1H, d, J=1.8 Hz), 7.34-7.38 (1H, m), 7.44-7.48(1H, m), 7.61-7.69 (4H, m), 8.16 (1H, d, J=1.8 Hz), 8.45 (1H, d, J=2.4Hz), 8.81 (1H, m), 9.91 (1H, s).

Reference Example 2485-(2-Methylphenyl)-1-{[3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrole-3-carbaldehyde

To a solution (30 mL) of 5-(2-methylphenyl)-1H-pyrrole-3-carbaldehyde(150 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 98 mg)at room temperature and the mixture was stirred for 30 min. 15-Crown-5(540 mg) was added dropwise and the mixture was stirred for 30 min,[3-(methylsulfonyl)benzene]sulfonyl chloride (413 mg) was added, and themixture was further stirred for 1 hr. 1 mol/L Hydrochloric acid wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was crystallized from ethyl acetate-diisopropyl ether=1:4 togive the title compound as colorless crystals (yield 309 mg, 95%).

¹H-NMR (CDCl₃) δ: 1.85 (3H, s), 3.03 (3H, s), 6.56 (1H, d, J=1.8 Hz),6.85-6.88 (1H, m), 7.09-7.18 (2H, m), 7.33-7.38 (1H, m), 7.57-7.65 (2H,m), 7.98-7.99 (1H, m), 8.14-8.18 (2H, m), 9.92 (1H, s).

Reference Example 2491-(Phenylsulfonyl)-5-(pyridin-2-yl)-1H-pyrrole-3-carbaldehyde

To a solution (16 mL) of 5-(pyridin-2-yl)-1H-pyrrole-3-carbaldehyde (80mg) in tetrahydrofuran was added sodium hydride (60% in oil, 56 mg) atroom temperature and the mixture was stirred for 30 min. 15-Crown-5 (307mg) was added dropwise and the mixture was stirred for 30 min.Benzenesulfonyl chloride (165 mg) was added, and the mixture was furtherstirred for 1 hr. Saturated brine was added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=4:1→1:1), andcrystallized from diisopropyl ether to give the title compound ascolorless crystals (yield 85 mg, 59%).

¹H-NMR (CDCl₃) δ: 6.86 (1H, d, J=1.8 Hz), 7.25-7.29 (1H, m), 7.50-7.55(3H, m), 7.61-7.67 (1H, m), 7.70-7.76 (1H, m), 7.83-7.87 (2H, m), 8.17(1H, d, J=1.8 Hz), 8.43-8.46 (1H, m), 9.90 (1H, s).

Reference Example 2501-[(3,4-Difluorophenyl)sulfonyl]-5-(pyridin-2-yl)-1H-pyrrole-3-carbaldehyde

To a solution (16 mL) of 5-(pyridin-2-yl)-1H-pyrrole-3-carbaldehyde (80mg) in tetrahydrofuran was added sodium hydride (60% in oil, 56 mg) atroom temperature and the mixture was stirred for 30 min. 15-Crown-5 (307mg) was added dropwise and the mixture was stirred for 30 min,3,4-difluorobenzenesulfonyl chloride (198 mg) was added, and the mixturewas further stirred for 1 hr. Saturated brine was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (eluent: hexane-ethyl acetate=4:1→1:1),and crystallized from diisopropyl ether to give the title compound ascolorless crystals (yield 114 mg, 70%).

¹H-NMR (CDCl₃) δ: 6.88 (1H, d, J=1.8 Hz), 7.29-7.38 (2H, m), 7.51-7.55(1H, m), 7.72-7.80 (2H, m), 7.85-7.92 (1H, m), 8.13 (1H, d, J=1.8 Hz),8.46-8.49 (1H, m), 9.90 (1H, s).

Reference Example 2511-(2,3-Dihydro-1,4-benzodioxin-5-ylsulfonyl)-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde

Using 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodiumhydride (60% in oil, 116 mg), 15-crown-5 (881 mg) and2,3-dihydro-1,4-benzodioxine-5-sulfonyl chloride (516 mg), a procedureas in Reference Example 219 was performed to give the title compound asa pale-yellow amorphous (yield 295 mg, 77%).

¹H-NMR (CDCl₃) δ: 2.03 (3H, s), 4.22-4.31 (4H, m), 6.75-6.82 (3H, m),7.04-7.07 (2H, m), 7.30-7.46 (3H, m), 8.00 (1H, s), 9.93 (1H, s).

Reference Example 2521-[(2,5-Dimethoxyphenyl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde

Using 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodiumhydride (60% in oil, 72 mg), 15-crown-5 (330 mg) and2,5-dimethoxybenzenesulfonyl chloride (355 mg), a procedure as inReference Example 219 was performed to give the title compound as apale-yellow powder (yield 330 mg, 86%).

¹H-NMR (CDCl₃) δ: 2.03 (3H, s), 3.51 (3H, s), 3.73 (3H, s), 6.56 (1H, d,J=3.0 Hz), 6.83-6.89 (3H, m), 7.02-7.06 (1H, m), 7.17-7.32 (3H, m), 8.11(1H, s), 9.96 (1H, s).

Reference Example 2531-(2,3-Dihydro-1,4-benzodioxin-6-ylsulfonyl)-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde

Using 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodiumhydride (60% in oil, 72 mg), 15-crown-5 (330 mg) and2,3-dihydro-1,4-benzodioxine-6-sulfonyl chloride (352 mg), a procedureas in Reference Example 219 was performed to give the title compound asa pale-yellow oil (yield 391 mg, about 100%).

¹H-NMR (CDCl₃) δ: 2.03 (3H, s), 4.22-4.31 (4H, s), 6.72-6.82 (3H, m),7.04-7.07 (2H, s), 7.30-7.43 (3H, s), 8.00 (1H, s), 9.94 (1H, s).

Reference Example 2544-Methyl-1-{[3-(methylsulfonyl)phenyl]sulfonyl}-5-phenyl-1H-pyrrole-3-carbaldehyde

Using 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodiumhydride (60% in oil, 60 mg), 15-crown-5 (0.30 mL) and[3-(methylsulfonyl)benzene]sulfonyl chloride (331 mg), a procedure as inReference Example 219 was performed to give the title compound as asolid (yield 191 mg, 47%).

¹H-NMR (CDCl₃) δ: 2.03 (3H, s), 3.01 (3H, s), 7.01-7.04 (2H, m),7.31-7.60 (5H, m), 7.92 (1H, m), 8.06 (1H, s), 8.12-8.14 (1H, m), 9.98(1H, s).

Reference Example 2554-Methyl-5-phenyl-1-(3-thienylsulfonyl)-1H-pyrrole-3-carbaldehyde

Using 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodiumhydride (60% in oil, 60 mg), 15-crown-5 (0.30 mL) and(3-thienyl)sulfonyl chloride (237 mg), a procedure as in ReferenceExample 219 was performed to give the title compound as a solid (yield290 mg, 88%).

¹H-NMR (CDCl₃) δ: 2.04 (3H, s), 6.91-6.93 (1H, s), 7.06-7.09 (2H, m),7.26-7.41 (5H, m), 8.03 (1H, s), 9.96 (1H, s).

Reference Example 2564-Methyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

4-Methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg) was dissolved intetrahydrofuran (10 mL), sodium hydride (60% in oil, 60 mg) was addedand the mixture was stirred at room temperature for 15 min. 15-Crown-5(0.30 mL) was added and the mixture was further stirred at the sametemperature for 15 min. 3-Pyridinesulfonyl chloride hydrochloride (231mg) was added and the reaction mixture was stirred at room temperaturefor 1 hr. Water was added, and the mixture was extracted with ethylacetate. The extract was washed with water and saturated brine, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=19:1→1:1) to give the title compound as acolorless solid (yield 172 mg, 53%).

¹H-NMR (CDCl₃) δ: 2.03 (3H, s), 7.01-7.04 (2H, m), 7.26-7.55 (5H, m),8.07 (1H, s), 8.47 (1H, m), 8.75-8.78 (1H, m), 9.97 (1H, s).

Reference Example 2574-Methyl-5-phenyl-1-(pyridin-2-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

By a reaction under similar conditions as in Reference Example 256 andusing 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodiumhydride (60% in oil, 60 mg), 15-crown-5 (0.30 mL) and 2-pyridinesulfonylchloride (231 mg), the title compound was obtained as an amorphous form(yield 262 mg, 80%).

¹H-NMR (CDCl₃) δ: 2.03 (3H, s), 6.92-6.95 (2H, m), 7.21-7.49 (5H, m),7.65-7.69 (1H, m), 8.14 (1H, s), 8.64-8.65 (1H, m), 9.98 (1H, s).

Reference Example 2581-[(1,2-Dimethyl-1H-imidazol-4-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde

By a reaction under similar conditions as in Reference Example 256 andusing 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodiumhydride (60% in oil, 60 mg), 15-crown-5 (0.30 mL) and(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl chloride (253 mg), the titlecompound was obtained as a colorless solid (yield 294 mg, 86%).

¹H-NMR (CDCl₃) δ: 2.05 (3H, s), 2.33 (3H, s), 3.40 (3H, s), 6.48 (1H,s), 7.11-7.14 (2H, m), 7.26-7.41 (3H, m), 8.08 (1H, s), 9.93 (1H, s).

Reference Example 2591-[(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde

By a reaction under similar conditions as in Reference Example 256 andusing 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodiumhydride (60% in oil, 60 mg), 15-crown-5 (0.30 mL) and(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl chloride (298 mg), thetitle compound was obtained as an oil (yield 379 mg, about 100%).

¹H-NMR (CDCl₃) δ: 1.74 (3H, s), 2.04 (3H, s), 3.69 (3H, s), 7.04-7.07(2H, m), 7.28-7.38 (3H, m), 8.09 (1H, s), 9.96 (1H, s).

Reference Example 2601-[(2,4-Dimethyl-1,3-thiazol-5-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde

By a reaction under similar conditions as in Reference Example 256 andusing 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodiumhydride (60% in oil, 60 mg), 15-crown-5 (0.30 mL) and(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl chloride (275 mg), the titlecompound was obtained as an oil (yield 27.8 mg, 8%).

¹H-NMR (CDCl₃) δ: 2.05 (3H, s), 2.10 (3H, s), 2.59 (3H, s), 7.07-7.10(2H, m), 7.31-7.40 (3H, m), 8.02 (1H, s), 9.96 (1H, s).

Reference Example 2615-(2-Fluorophenyl)-4-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

By a similar procedure as in Reference Example 256 and using5-(2-fluorophenyl)-4-methyl-1H-pyrrole-3-carbaldehyde (301 mg), sodiumhydride (60% in oil, 179 mg), 15-crown-5 (0.88 mL) andpyridin-3-ylsulfonyl chloride (476 mg), the title compound was obtainedas white crystals (yield 440 mg, 87%).

¹H-NMR (CDCl₃) δ: 2.02 (3H, s), 6.98-7.04 (1H, m), 7.13-7.24 (2H, m),7.33-7.38 (1H, m), 7.43-7.51 (1H, m), 7.65-7.69 (1H, m), 8.09 (1H, s),8.54-8.55 (1H, m), 8.80-8.82 (1H, m), 9.98 (1H, s).

Reference Example 2622-[(2-Bromo-4-formyl-1H-pyrrol-1-yl)sulfonyl]benzonitrile

Using 5-bromo-1H-pyrrole-3-carbaldehyde (801 mg), sodium hydride (60% inoil, 282 mg), 15-crown-5 (1.57 g) and (2-cyanobenzene)sulfonyl chloride(1.43 g), a procedure as in Reference Example 146 was performed to givethe title compound as a white solid (yield 1.09 g, 70%).

¹H-NMR (CDCl₃) δ: 6.79 (1H, d, J=2.2 Hz), 7.85-7.96 (3H, m), 8.34 (1H,d, J=2.2 Hz), 8.44-8.49 (1H, m), 9.81 (1H, s).

Reference Example 263 2-Methyl-1H-pyrrole-3-carbaldehyde

To a solution of 2-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde(4.59 g) in tetrahydrofuran (20 mL) and methanol (5 mL) was added 8mol/L aqueous sodium hydroxide solution (2.5 mL) at 0° C., and thereaction mixture was stirred at the same temperature for 30 min. Waterwas added to the reaction mixture, and the mixture was extracted withethyl acetate. The extract was washed with saturated aqueous sodiumhydrogencarbonate solution, water and saturated brine, dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=2:1) to give the title compound as a whitesolid (yield 1.06 g, 54%).

¹H-NMR (CDCl₃) δ: 2.56 (3H, s), 6.58-6.59 (1H, m), 6.65-6.67 (1H, m),8.52 (1H, brs), 9.89 (1H, s).

Reference Example 2642-Methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

By a similar operation as in Reference Example 146 and using2-methyl-1H-pyrrole-3-carbaldehyde (1.10 g), sodium hydride (60% in oil,1.20 g), 15-crown-5 (6.0 mL) and pyridin-3-ylsulfonyl chloride (3.22 g),the title compound was obtained as white crystals (yield 1.10 g, 44%).

¹H-NMR (CDCl₃) δ: 2.66 (3H, s), 6.68 (1H, d, J=3.9 Hz), 7.34 (1H, d,J=3.9 Hz), 7.51-7.55 (1H, m), 8.09-8.13 (1H, m), 8.89-8.91 (1H, m),9.10-9.11 (1H, m), 9.90 (1H, s).

Reference Example 2655-Bromo-2-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde

To a solution of 2-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde(2.00 g) in N,N-dimethylformamide (20 mL) was added N-bromosuccinimide(1.56 g) at 0° C., and the mixture was stirred at room temperature for 1hr. Water was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedaqueous sodium hydrogencarbonate solution, water and saturated brine,dried over anhydrous sodium sulfate, filtrated, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=3:1) to give the titlecompound as a white solid (yield 2.28 g, 86%).

¹H-NMR (CDCl₃) δ: 2.86 (3H, s), 6.68 (1H, s), 7.57-7.62 (2H, m),7.68-7.73 (1H, m), 7.94-7.97 (2H, m), 9.90 (1H, s)

Reference Example 2665-Bromo-2-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

To a solution of2-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (974 mg) inN,N-dimethylformamide (10 mL) was added N-bromosuccinimide (1.17 g) at0° C., and the mixture was stirred at room temperature for 1 hr. Waterwas added to the reaction mixture, and the mixture was extracted withethyl acetate. The extract was washed with saturated aqueous sodiumhydrogencarbonate solution, water and saturated brine, dried overanhydrous magnesium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=2:1) to give the title compound as whitecrystals (yield 675 mg, 53%).

¹H-NMR (CDCl₃) δ: 2.89 (3H, s), 6.18 (1H, s), 7.53-7.57 (1H, m),8.21-8.26 (1H, m), 8.91-8.93 (1H, m), 9.17-9.18 (1H, m), 9.92 (1H, s).

Reference Example 2672-Methyl-1-(phenylsulfonyl)-5-(3-pyridyl)-1H-pyrrole-3-carbaldehyde

Under an argon atmosphere, a suspension of5-bromo-2-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (497 mg),3-pyridineboronic acid (376 mg), sodium carbonate (481 mg) andtetrakis(triphenylphosphine)palladium (89.2 mg) in 1,2-dimethoxyethane(12 mL) and water (6 mL) was stirred at 80° C. for 1 hr. The reactionmixture was cooled to room temperature, water was added, and the mixturewas extracted with ethyl acetate. The extract was washed with saturatedaqueous sodium hydrogencarbonate solution, water and saturated brine,dried over anhydrous sodium sulfate, filtrated, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=1:4) to give the titlecompound as a white solid (yield 353 mg, 72%).

¹H-NMR (CDCl₃) δ: 2.89 (3H, s), 6.56 (1H, s), 7.24-7.33 (1H, m),7.39-7.48 (4H, m), 7.59-7.65 (1H, m), 7.68-7.72 (1H, m), 8.32 (1H, d,J=2.1 Hz), 8.62 (1H, dd, J=1.5, 4.8 Hz), 10.02 (1H, s).

Reference Example 2682-Methyl-5-(1-methyl-1H-pyrazol-4-yl)-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde

Using 5-bromo-2-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (497mg), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)-1H-pyrazole(630 mg), sodium carbonate (480 mg) andtetrakis(triphenylphosphine)palladium (88.3 mg), a procedure as inReference Example 267 was performed to give the title compound as awhite solid (yield 466 mg, 94%).

¹H-NMR (CDCl₃) δ: 2.90 (3H, s), 3.91 (3H, s), 6.45 (1H, s), 7.24 (1H,s), 7.35 (1H, s), 7.39-7.46 (4H, m), 7.56-7.61 (1H, m), 10.00 (1H, s).

Reference Example 2694-Methyl-1-(phenylsulfonyl)-5-(3-thienyl)-1H-pyrrole-3-carbaldehyde

Under an argon atmosphere, a suspension of5-bromo-4-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (656 mg),3-thiopheneboronic acid (511 mg),dichloro[bis(triphenylphosphine)]palladium (70 mg) and sodium carbonate(636 mg) in 1,2-dimethoxyethane (10 mL)-water (3 mL) was stirred at 100°C. for 2 hr. After cooling, the reaction mixture was filtered throughcelite, and celite was washed with ethyl acetate. The organic layer wasseparated from the filtrate, washed with water and saturated brine,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=19:1→7:3) to give the title compound as acolorless oil (yield 549 mg, 83%).

¹H-NMR (CDCl₃) δ: 2.06 (3H, s), 6.85 (1H, m), 6.97 (1H, m), 7.26-7.37(5H, m), 7.55-7.59 (1H, m), 8.06 (1H, s), 9.94 (1H, s).

Reference Example 2701-[5-Bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine

To a solution (60 mL) of5-bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (3.5 g) in methanolwere added methylammonium chloride (7.5 g) and sodium cyanoborohydride(2.4 g), and the mixture was stirred at room temperature for 1 hr. Thereaction mixture was concentrated under reduced pressure, saturatedaqueous sodium hydrogencarbonate solution was added to the residue, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated aqueous sodium hydrogencarbonate solution, water andsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to give the title compound as a brown oil (yield4.4 g, about 100%).

¹H-NMR (CDCl₃) δ: 2.47 (3H, s), 2.98 (1H, brs), 3.66 (2H, s), 6.35 (1H,d, J=2.4 Hz), 7.51-7.57 (3H, m), 7.61-7.68 (1H, m), 7.93-7.97 (2H, m).

Reference Example 2711-[5-Bromo-4-isopropyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine

Using methyl5-bromo-4-isopropyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (4.8 g),and a 1.5 mol/L solution (50 mL) of diisobutylaluminum hydride intoluene, tetra-n-propylammonium perruthenate (218 mg),N-methylmorpholine N-oxide (1.6 g) and molecular sieves 4A powder (2.5g), a procedure as in Reference Example 6 was performed to give crude5-bromo-4-isopropyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (3.83g) as an oil. Furthermore, using 40% methylamine methanol solution (877mg), sodium borohydride (474 mg) and crude5-bromo-4-isopropyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (3.83g), a procedure as in Reference Example 66 was performed to give thetitle compound as a colorless oil (yield 502 mg, 11%).

¹H-NMR (CDCl₃) δ: 1.18 (6H, d, J=7.2 Hz), 1.50 (1H, br), 2.48 (3H, s),2.87-2.96 (1H, m), 3.62 (2H, s), 7.43 (1H, s), 7.49-7.54 (2H, m),7.60-7.64 (1H, m), 7.88-7.92 (2H, m).

Reference Example 272 tert-Butyl{[5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

To a solution of1-[5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (4.4g) in ethyl acetate (60 mL) was added di-tert-butyl bicarbonate (2.8mL), and the mixture was stirred at room temperature for 14 hr.Saturated aqueous sodium hydrogencarbonate solution was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theextract was washed with aqueous sodium hydrogencarbonate solution andsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=4:1) to give the titlecompound as a colorless oil (yield 3.4 g, 73%).

¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 2.79 (3H, brs), 4.17 (2H, brs), 6.24(1H, brs), 7.35 (1H, brs), 7.51-7.57 (2H, m), 7.62-7.68 (1H, m),7.90-7.94 (2H, m).

Reference Example 273 tert-Butyl{[5-bromo-1-(2-cyanophenyl)sulfonyl-1H-pyrrol-3-yl]methyl}methylcarbamate

To a solution of2-[(2-bromo-4-formyl-1H-pyrrol-1-yl)sulfonyl]benzonitrile (1.18 g) intetrahydrofuran (10 mL) and methanol (10 mL) was added 40% methylaminemethanol solution (3 mL), and the reaction mixture was stirred at roomtemperature for 1 hr. Sodium borohydride (152 mg) was added to thereaction mixture and the mixture was further stirred for 15 min. Themixture was concentrated under reduced pressure. Water (50 mL) was addedto the residue, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated aqueous sodium hydrogencarbonatesolution, water and saturated brine, dried over anhydrous sodiumsulfate, filtrated and the filtrate was concentrated under reducedpressure. The residue was dissolved in ethyl acetate (10 mL),di-tert-butyl dicarbonate (0.8 mL) was added, and the mixture wasstirred at room temperature for 2 days. Water (100 mL) was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated aqueous sodium hydrogencarbonatesolution, water and saturated brine, filtrated, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=2:1) to give thetitle compound as a yellow oil (yield 296 mg, 38%).

¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 2.81 (3H, brs), 4.21 (2H, brs), 6.32(1H, brs), 7.62 (1H, s), 7.76-7.89 (3H, m), 8.3-8.39 (1H, m).

Reference Example 274 tert-Butyl[(5-bromo-1-{[3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrol-3-yl)methyl]carbamate

Using5-bromo-1-{3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrole-3-carbaldehyde(4.88 g), a procedure as in Reference Example 273 was performed to givethe title compound as a yellow oil (yield 0.96 g, 27%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.80 (3H, s), 3.10 (3H, s), 4.18 (2H,brs), 6.28 (1H, brs), 7.35 (1H, d, J=1.8 Hz), 7.79 (1H, t, J=7.8 Hz),8.18-8.24 (2H, m), 8.51-8.52 (1H, m).

Reference Example 275 tert-Butyl{[5-bromo-4-ethyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

Using 5-bromo-4-ethyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (1.91g), a procedure as in Reference Example 273 was performed to give thetitle compound as a brown oil (yield 1.13 g, 44%).

¹H-NMR (CDCl₃) δ: 0.96 (3H, brt, J=7.5 Hz), 1.49 (9H, s), 2.32 (2H, q,J=7.5 Hz), 2.74 (3H, brs), 4.26 (2H, brs), 7.35 (1H, s), 7.50-7.55 (2H,m), 7.61-7.64 (1H, m), 7.88-7.91 (2H, m).

Reference Example 276 tert-Butyl{[5-bromo-4-isopropyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

Using1-[5-bromo-4-isopropyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine(502 mg) and di-tert-butyl bicarbonate (442 mg), a procedure as inReference Example 55 was performed to give the title compound as acolorless oil (yield 596 mg, 94%).

¹H-NMR (CDCl₃) δ: 1.15 (6H, d, J=7.2 Hz), 1.47 (9H, brs), 2.80 (3H,brs), 2.88-2.95 (1H, m), 4.30 (2H, brs), 7.30 (1H, s), 7.49-7.56 (2H,m), 7.61-7.66 (1H, m), 7.87-7.90 (2H, m).

Reference Example 277 tert-Butyl{[4-ethyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

Using tert-butyl{[5-bromo-4-ethyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(1.13 g), phenylboronic acid (462 mg), sodium carbonate (789 mg) andtetrakis(triphenylphosphine)palladium (431 mg), a procedure as inReference Example 56 was performed to give the title compound as a brownoil (yield 602 mg, 54%).

¹H-NMR (CDCl₃) δ: 0.84 (3H, brt, J=7.5 Hz), 1.49 (9H, s), 2.15 (2H, q,J=7.5 Hz), 2.82 (3H, s), 4.32 (2H, brs), 7.01-7.04 (2H, m), 7.26-7.36(8H, m), 7.48-7.52 (1H, m).

Reference Example 278 tert-Butyl{[4-isopropyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

Using tert-butyl{[5-bromo-4-isopropyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(596 mg), phenylboronic acid (307 mg),tetrakis(triphenylphosphine)palladium (218 mg) and sodium carbonate (401mg), a procedure as in Reference Example 56 was performed to give thetitle compound as a pale-red oil (yield 218 mg, 37%).

¹H-NMR (CDCl₃) δ: 0.96 (6H, d, J=7.2 Hz), 1.50 (9H, brs), 2.55-2.65 (1H,m), 2.89 (3H, s), 4.39 (2H, br), 6.90-7.00 (2H, m), 7.19-7.36 (8H, m),7.49-7.53 (1H, m).

Reference Example 279 Methyl2-[(4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoate

Using methyl2-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzoate(367 mg) and di-tert-butyl dicarbonate (250 mg), a procedure as inReference Example 55 was performed to give the title compound as acolorless oil (yield 524 mg, about 100%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.85 (3H, s), 3.88 (3H, s), 4.27 (2H,br), 6.15 (1H, brs), 6.98-7.01 (1H, s), 7.17-7.32 (7H, m), 7.50-7.52(2H, m).

Reference Example 280 Methyl3-[(4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoate

Using methyl3-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzoate(577 mg) and di-tert-butyl dicarbonate (393 mg), a procedure as inReference Example 55 was performed to give the title compound as acolorless oil (yield 710 mg, 98%).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.80 (3H, s), 3.91 (3H, s), 4.22 (2H,brs), 6.10 (1H, brs), 7.19-7.23 (2H, m), 7.27-7.50 (6H, m), 7.97-7.98(1H, m), 8.15-8.18 (1H, m).

Reference Example 2812-[(4-{[(tert-Butoxycarbonyl)(methyl)amino]methyl}-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoicacid

Methyl2-[(4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoate(524 mg) was dissolved in tetrahydrofuran (5 mL) and methanol (3 mL),and 1 mol/L aqueous sodium hydroxide solution (3 mL) was added at 0° C.The mixture was stirred at 0° C. for 1 hr, and at room temperature for16 hr, cooled again to 0° C., acidified with 1 mol/L hydrochloric acid,and the mixture was extracted with ethyl acetate. The extract was washedwith water and saturated brine, dried over anhydrous magnesium sulfateand the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=1:1→0:1) to give the title compound as a colorless amorphous(yield 256 mg, 50%).

¹H-NMR (CDCl₃) δ: 1.53 (9H, brs), 3.08 (3H, brs), 4.27 (2H, brs), 6.06(1H, br), 7.00-7.52 (10H, m), 1H not detected.

Reference Example 2823-[(4-{[(tert-Butoxycarbonyl)(methyl)amino]methyl}-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoicacid

Methyl3-[(4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoate(710 mg) was dissolved in tetrahydrofuran (5 mL) and methanol (3 mL),and 1 mol/L aqueous sodium hydroxide solution (3 mL) was added at 0° C.The mixture was stirred at 0° C. for 1 hr, and at room temperature for 2hr, cooled again to 0° C., acidified with 1 mol/L hydrochloric acid, andthe mixture was extracted with ethyl acetate. The extract was washedwith water and saturated brine, dried over anhydrous magnesium sulfateand the solvent was evaporated under reduced pressure. The residualcrystals were washed with a mixed solvent of isopropyl ether and hexaneto give the title compound as colorless crystals (yield 577 mg, 83%).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.81 (3H, brs), 4.22 (2H, br), 6.11 (1H,br), 7.16-7.52 (8H, m), 8.03 (1H, br), 8.19-8.22 (1H, m), 1H notdetected.

Reference Example 283 tert-Butyl[(1-{[3-(aminocarbonyl)phenyl]sulfonyl}-5-phenyl-1H-pyrrol-3-yl)methyl]methylcarbamate

To a solution (5 mL) of3-[(4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoicacid (205 mg) in N,N-dimethylformamide were added1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (125 mg)and 1-hydroxy-1H-benzotriazole ammonium salt (100 mg) at roomtemperature. The mixture was stirred at the same temperature for 1 hr,water was added and the mixture was extracted with ethyl acetate. Theextract was washed with water and saturated brine, dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1→1:1→1:4) to give the title compound as acolorless oil (yield 193 mg, 94%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.85 (3H, brs), 4.23 (2H, brs), 5.61(1H, br), 6.10 (1H, d, J=1.8 Hz), 7.21-7.51 (9H, m), 8.07 (1H, d, J=7.5Hz), 1H not detected.

Reference Example 284 tert-Butyl{[1-({3-[(cyclopropylamino)carbonyl]phenyl}sulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}methylcarbamate

To a solution (5 mL) of3-[(4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoicacid (150 mg) in N,N-dimethylformamide were added1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (92 mg),1-hydroxy-1H-benzotriazole (73 mg) and cyclopropylamine (27 mg) at roomtemperature. After stirring at the same temperature for 30 min, waterwas added and the mixture was extracted with ethyl acetate. The extractwas washed with water and saturated brine, dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→4:1) to give the title compound as a colorlessamorphous (yield 162 mg, quantitative).

¹H-NMR (CDCl₃) δ: 0.60-0.64 (2H, m), 0.86-0.95 (2H, m), 1.46 (9H, s),2.81 (3H, s), 2.80-2.90 (1H, m), 4.22 (2H, m), 5.90 (1H, br), 6.09 (1H,d, J=1.5 Hz), 7.21-7.52 (9H, m), 8.03 (1H, d, J=7.2 Hz).

Reference Example 285 tert-Butylmethyl{[1-({3-[(methylamino)carbonyl]phenyl}sulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}carbamate

Using3-[(4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoicacid (150 mg) and 2 mol/L methylamine-tetrahydrofuran solution (5 mL), aprocedure as in Reference Example 284 was performed to give the titlecompound as a colorless oil (yield 99 mg, 64%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, brs), 2.84 (3H, brs), 2.97 (3H, d, J=4.5Hz), 4.22 (2H, brs), 6.09 (1H, d, J=1.8 Hz), 7.21-7.44 (10H, m), 8.03(1H, br).

Reference Example 286 tert-Butyl{[1-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}methylcarbamate

To a suspension (3 mL) of sodium hydride (60% in oil, 36 mg) intetrahydrofuran was added a solution (2 mL) of tert-butylmethyl{[1-({3-[(methylamino)carbonyl]phenyl}sulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}carbamate(240 mg) in N,N-dimethylformamide at room temperature. After stirring atthe same temperature for 15 min, iodomethane (106 mg) was added, and themixture was stirred for 30 min. Water was added to the reaction mixture,and the mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=4:1→1:1) to givethe title compound as a colorless oil (yield 168 mg, 68%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.81 (6H, brs), 3.08 (3H, brs), 4.22(2H, brs), 6.11 (1H, br), 7.22-7.39 (9H, m), 7.58-7.61 (1H, m).

Reference Example 287 tert-Butylmethyl[(1-{[3-(morpholin-4-ylcarbonyl)phenyl]sulfonyl}-5-phenyl-1H-pyrrol-3-yl)methyl]carbamate

Using3-[(4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoicacid (150 mg) and morpholine (42 mg), a procedure as in ReferenceExample 284 was performed to give the title compound as a colorless oil(yield 164 mg, 95%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.81 (3H, brs), 3.21 (2H, br), 3.57 (2H,br), 3.73 (4H, br), 4.22 (2H, br), 6.12 (1H, br), 7.23-7.43 (9H, m),7.58-7.61 (1H, m).

Reference Example 288 tert-Butyl[(1-{[3-(1-hydroxy-1-methylethyl)phenyl]sulfonyl}-5-phenyl-1H-pyrrol-3-yl)methyl]carbamate

To a solution of methyl3-[(4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoate(513 mg) in tetrahydrofuran (5 mL) was added an about 1 mol/L solution(4.5 mL) of methyllithium in diethyl ether at −78° C., and the mixturewas stirred at the same temperature for 1 hr. Water (20 mL) was added tothe reaction mixture, and the mixture was extracted with ethyl acetate.The extract was washed with water and saturated brine, and dried overanhydrous magnesium sulfate. The mixture was filtrated, and the filtratewas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (eluent: hexane-ethyl acetate=2:1) togive the title compound as a yellow oil (yield 337 mg, 66%).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 1.58 (6H, s), 1.89 (1H, brs), 2.80 (3H,s), 4.23 (2H, brs), 6.09 (1H, d, J=2.1 Hz), 7.22-7.38 (8H, m), 7.42-7.43(1H, m), 7.60-7.63 (1H, m).

Reference Example 289 tert-Butyl({1-[(4-cyano-3-fluorophenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)carbamate

Using2-fluoro-4-[(4-formyl-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzonitrile (223mg), a procedure as in Reference Example 273 was performed to give thetitle compound as a yellow oil (yield 57.3 mg, 24%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.83 (3H, s), 4.23 (2H, brs), 6.17 (1H,s), 7.08-7.11 (1H, m), 7.19-7.23 (3H, m), 7.26-7.27 (1H, m), 7.32-7.42(3H, m), 7.57-7.61 (1H, m).

Reference Example 290 tert-Butyl({1-[(3-cyanophenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)methylcarbamate

To a solution (16 mL) of3-({(methylamino)methyl-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzonitrile(0.23 g) in ethyl acetate was added di-tert-butyl bicarbonate (0.19 g),and the mixture was stirred at room temperature for 16 hr. The reactionmixture was diluted with ethyl acetate, washed successively withsaturated aqueous sodium hydrogencarbonate solution and saturated brine,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=4:1→2:1) to give the title compound as anoil (yield 0.30 g, about 100%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.83 (3H, s), 4.23 (2H, brs), 6.14 (1H,s), 7.16-7.22 (2H, m), 7.29-7.38 (3H, m), 7.40-7.49 (3H, m), 7.55 (1H,ddd, J=1.41, 1.55, 8.15 Hz), 7.77 (1H, dt, J=1.37, 7.63 Hz).

Reference Example 291 tert-Butylmethyl[(5-phenyl-1-{[3-(1H-tetrazol-5-yl)phenyl]sulfonyl}-1H-pyrrol-3-yl)methyl]carbamate

A mixture of tert-butyl({1-[(3-cyanophenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)methylcarbamate(0.29 g), sodium azide (70 mg), triethylamine hydrochloride (0.19 g) andtoluene (10 ml) was heated under reflux for 7 days. After cooling thereaction mixture, ethyl acetate was added to the mixture, and themixture was washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: ethylacetate-methanol=10:1) to give the title compound as an oil (yield 0.052g, 16%).

¹H-NMR (CDCl₃) δ: 1.55 (9H, s), 3.04 (3H, s), 4.28 (2H, s), 6.04 (1H,s), 7.14 (2H, s), 7.23-7.35 (6H, m), 7.44 (1H, t, J=7.9 Hz), 7.85 (1H,s), 8.39 (1H, s).

Reference Example 292 tert-Butyl[(5-bromo-1H-pyrrol-3-yl)methyl]methylcarbamate

tert-Butyl{[5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (1.0g) was dissolved in a mixed solvent of tetrahydrofuran (15 mL) andmethanol (5 mL), and 8 mol/L aqueous sodium hydroxide solution (1.5 mL)was added dropwise at not more than 10° C. After stirring at the sametemperature for 4 hr, water was added to the residue and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by basic silica gel columnchromatography (eluent: hexane-ethyl acetate=9:1→4:1) to give the titlecompound as a pale-yellow oil (yield 410 mg, 61%).

¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 2.79 (3H, s), 4.17 (2H, s), 6.09 (1H,brs), 6.64 (1H, brs), 8.07 (1H, br).

Reference Example 293 tert-Butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

A solution (3 mL) of tert-butyl[(5-bromo-1H-pyrrol-3-yl)methyl]methylcarbamate (410 mg) inN,N-dimethylformamide was added to a suspension (10 mL) of sodiumhydride (60% in oil, 204 mg) in tetrahydrofuran at 0° C., 15-crown-5(938 mg) and pyridin-3-ylsulfonyl chloride hydrochloride (456 mg) wereadded at the same temperature. After stirring at room temperature for 2hr, water was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedaqueous sodium hydrogencarbonate solution, water and saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=8:1→3:1) to give the title compound as apale-yellow powder (yield 522 mg, 85%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.80 (3H, brs), 4.18 (2H, brs), 6.28(1H, brs), 7.35 (1H, brs), 7.48-7.52 (1H, m), 8.18-8.22 (1H, m),8.85-8.88 (1H, m), 9.12-9.13 (1H, m).

Reference Example 294 tert-Butyl{[(2-cyanophenyl)sulfonyl-5-(3-pyridyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

Using tert-butyl{[5-bromo-1-(2-cyanophenyl)sulfonyl-1H-pyrrol-3-yl]methyl}methylcarbamate(296 mg), 3-pyridineboronic acid (162 mg), sodium carbonate (208 mg) andtetrakis(triphenylphosphine)palladium (38.2 mg), a procedure as inReference Example 267 was performed to give the title compound as awhite solid (yield 187 mg, 63%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.86 (3H, s), 4.28 (2H, brs), 6.25 (1H,brs), 7.24-7.31 (2H, m), 7.45-7.51 (1H, m), 7.62-7.79 (4H, m), 8.15 (1H,d, J=1.8 hz), 8.57-8.59 (1H, m).

Reference Example 295 tert-Butylmethyl[(1-{[3-(methylsulfonyl)phenyl]sulfonyl}-5-(3-thienyl)-1H-pyrrol-3-yl)methyl]carbamate

Using tert-butyl[(5-bromo-1-{[3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrol-3-yl)methyl]methylcarbamate(437 mg), 3-thiopheneboronic acid (223 mg), sodium carbonate (275 mg)and tetrakis(triphenylphosphine)palladium (50.8 mg), a procedure as inReference Example 267 was performed to give the title compound as awhite solid (yield 305 mg, 69%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.82 (3H, s), 3.00 (3H, s), 4.22 (2H,brs), 6.18 (1H, brs), 7.05-7.07 (1H, m), 7.19-7.20 (1H, m), 7.26-7.31(2H, m), 7.55-7.61 (2H, m), 7.95-7.96 (1H, m), 8.06-8.09 (1H, m).

Reference Example 296 tert-Butyl[(1-{[3-(methylsulfonyl)phenyl]sulfonyl}-5-(3-pyridyl)-1H-pyrrol-3-yl)methyl]methylcarbamate

Using tert-butyl[(5-bromo-1-{[3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrol-3-yl)methyl]methylcarbamate(459 mg), 3-pyridineboronic acid (222 mg), sodium carbonate (287 mg) andtetrakis(triphenylphosphine)palladium (53.1 mg), a procedure as inReference Example 267 was performed to give the title compound as awhite solid (yield 305 mg, 67%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.82 (3H, s), 3.04 (3H, s), 4.24 (2H,brs), 6.22 (1H, brs), 7.36-7.39 (2H, m), 7.61-7.64 (2H, m), 7.75-7.79(1H, m), 7.86 (1H, s), 8.09-8.13 (1H, m), 8.26-8.27 (1H, m), 8.62-8.64(1H, m).

Reference Example 297 tert-Butyl{[1-(2-chloro-3-pyridinesulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}methylcarbamate

1-(2-Chloro-3-pyridinesulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde (443mg) was dissolved in absolute tetrahydrofuran (5 mL), a 2 mol/L solution(0.74 mL) of methylamine in tetrahydrofuran was added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasadded to a solution of sodium borohydride (97 mg) in methanol (2.5 mL),and the mixture was stirred at the same temperature for 20 min. Thereaction mixture was diluted with ethyl acetate, washed successivelywith saturated aqueous sodium hydrogencarbonate solution, water andsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was dissolvedin tetrahydrofuran (20 mL), di-tert-butyl bicarbonate (1.40 g), sodiumhydrogencarbonate (0.54 g) and water (13 mL) were added, and the mixturewas stirred at room temperature for 20 min. The reaction mixture wasdiluted with ethyl acetate, washed successively with saturated aqueoussodium hydrogencarbonate solution, water and saturated brine and driedover anhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=19:1→3:1) to give the titlecompound as a solid (yield 361 mg, 61%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.87 (3H, s), 4.29 (2H, s), 6.30-6.32(1H, m), 6.95-7.00 (1H, m), 7.06-7.33 (5H, m), 7.51-7.56 (2H, m),8.38-8.41 (1H, m).

Reference Example 298 tert-Butyl{[1-(6-chloro-5-methyl-3-pyridinesulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}methylcarbamate

1-[(6-Chloro-5-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde(244 mg) was dissolved in absolute tetrahydrofuran (6.8 mL), a 2 mol/Lsolution (0.34 mL) of methylamine in tetrahydrofuran was added, and themixture was stirred at room temperature for 4 hr. The reaction mixturewas added to a solution of sodium borohydride (51 mg) in methanol (3mL), and the mixture was stirred at the same temperature for 3 min.di-tert-Butyl bicarbonate (654 mg) was added, and water (5 mL) andsodium hydrogencarbonate (420 mg) were added 3 min later. The mixturewas further stirred at room temperature for 30 min, water was added tothe reaction mixture, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=19:1→3:1) to give the title compound as anoil (yield 247 mg, 77%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.28 (3H, s), 2.82 (3H, s), 4.24-4.28(2H, m), 6.15 (1H, s), 7.23-7.42 (7H, m), 8.15 (1H, s).

Reference Example 299 tert-Butyl({[1-(6-chloropyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)methylcarbamate

1-[(6-Chloropyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde(1.27 g) was dissolved in absolute tetrahydrofuran (20 mL), a 2 mol/Lsolution (2.1 mL) of methylamine in tetrahydrofuran was added, and themixture was stirred at room temperature for 30 min. The reaction mixturewas added to a solution of sodium borohydride (277 mg) in methanol (10mL), and the mixture was stirred at the same temperature for 20 min. Thereaction mixture was diluted with ethyl acetate, washed successivelywith saturated aqueous sodium hydrogencarbonate solution, water andsaturated brine and dried over anhydrous magnesium sulfate.di-tert-Butyl bicarbonate (3.99 g) was added, and the solvent wasevaporated under reduced pressure. The residue was dissolved intetrahydrofuran (30 mL), sodium hydrogencarbonate (1.53 g) and water (36mL) was added, and the mixture was stirred at room temperature for 30min. The reaction mixture was diluted with ethyl acetate, washedsuccessively with saturated aqueous sodium hydrogencarbonate solution,water and saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=19:1→3:1) to give the title compound as a solid (yield 544 mg,32%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.82 (3H, s), 4.23 (2H, s), 6.16 (1H,s), 7.23-7.49 (8H, m), 8.28 (1H, s).

Reference Example 300 tert-Butylmethyl({[1-(6-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)carbamate

Under an argon atmosphere, a mixture of tert-butyl({[1-(6-chloropyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)methylcarbamate(100 mg), methylboronic acid (14 mg),tetrakis(triphenylphosphine)palladium (25 mg), potassium carbonate (90mg) and dioxane (3 mL) was stirred at 80° C. for 24 hr. Methylboronicacid (14 mg) and tetrakis(triphenylphosphine)palladium (25 mg) wereadded, and the mixture was stirred at 90° C. for 24 hr. Methylboronicacid (14 mg), tetrakis(triphenylphosphine)palladium (25 mg), potassiumcarbonate (90 mg) and dioxane (2 mL) were added, and the mixture wasstirred at 90° C. for 24 hr. The reaction mixture was diluted with ethylacetate, washed successively with saturated aqueous sodiumhydrogencarbonate solution, water and saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=19:1→1:1) to give the titlecompound as an oil (yield 85.8 mg, 36%).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.58 (3H, s), 2.81 (3H, s), 4.20-4.23(2H, m), 6.13 (1H, s), 7.07-7.10 (1H, m), 7.24-7.42 (7H, m), 8.39 (1H,s).

Reference Example 301 tert-Butylmethyl{[1-(pyridin-3-ylsulfonyl)-5-(3-thienyl)-1H-pyrrol-3-yl]methyl}carbamate

Under an argon atmosphere, a suspension of tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(232 mg), 3-thienylboronic acid (138 mg),tetrakis(triphenylphosphine)palladium (31.3 mg) and sodium carbonate(175 mg) in 1,2-dimethoxyethane (10 mL) and water (5 mL) was stirred at105° C. for 1 hr. The reaction mixture was allowed to cool to roomtemperature, water was added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The extract was washed with saturatedaqueous sodium hydrogencarbonate solution, water and saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=1:1) to give the title compound as apale-yellow oil (yield 189 mg, 81%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.82 (3H, brs), 4.22 (2H, brs), 6.17(1H, brs), 7.04-7.06 (1H, m), 7.16-7.17 (1H, m), 7.25-7.32 (3H, m),7.57-7.61 (1H, m), 8.56 (1H, d, J=2.4 Hz), 8.71-8.73 (1H, m).

Reference Example 302 tert-Butyl{[5-(4-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

By a similar operation as in Reference Example 301 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(300 mg), (4-fluorophenyl)boronic acid (195 mg),tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222mg), the title compound was obtained as a pale-yellow oil (yield 293 mg,94%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.81 (3H, brs), 4.22 (2H, brs), 6.12(1H, brs), 7.00-7.06 (2H, m), 7.18-7.31 (4H, m), 7.56-7.60 (1H, m),8.54-8.55 (1H, m), 8.73-8.75 (1H, m).

Reference Example 303 tert-Butylmethyl{[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate

By a similar operation as in Reference Example 301 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(300 mg), (2-methylphenyl)boronic acid (190 mg),tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222mg), the title compound was obtained as a pale-yellow oil (yield 210 mg,68%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 1.92 (3H, s), 2.84 (3H, brs), 4.26 (2H,brs), 6.07 (1H, d, J=1.2 Hz), 6.87-6.89 (1H, m), 7.09-7.19 (2H, m),7.26-7.35 (3H, m), 7.58-7.62 (1H, m), 8.54-8.55 (1H, m), 8.75-8.77 (1H,m).

Reference Example 304 tert-Butyl{[5-(4-fluoro-2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

Using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(300 mg), (4-fluoro-2-methylphenyl)boronic acid (215 mg),tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222mg), a procedure as in Reference Example 301 was performed to give thetitle compound as a pale-yellow oil (yield 216 mg, 67%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 1.92 (3H, s), 2.84 (3H, brs), 4.25 (2H,brs), 6.05 (1H, br), 6.79-6.91 (3H, m), 7.30-7.35 (2H, m), 7.61-7.65(1H, m), 8.58-8.59 (1H, m), 8.77-8.79 (1H, m).

Reference Example 305 tert-Butylmethyl{[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate

Using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(300 mg), (4-methyl-3-thienyl)boronic acid (198 mg),tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222mg), a procedure as in Reference Example 301 was performed to give thetitle compound as a pale-yellow oil (yield 200 mg, 64%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 1.81 (3H, s), 2.83 (3H, brs), 4.26 (2H,brs), 6.10 (1H, br), 6.90 (1H, br), 7.02-7.03 (1H, m), 7.26-7.35 (2H,m), 7.61-7.65 (1H, m), 8.58-8.59 (1H, m), 8.75-8.77 (1H, m).

Reference Example 306 tert-Butyl{[5-(3-cyanophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

By a similar operation as in Reference Example 301 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(300 mg), (3-cyanophenyl)boronic acid (205 mg),tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222mg), the title compound was obtained as a pale-yellow oil (yield 298 mg,94%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.81 (3H, brs), 4.22 (2H, brs), 6.21(1H, br), 7.31-7.35 (2H, m), 7.46-7.69 (6H, m), 8.56 (1H, d, J=1.8 Hz),8.76-8.78 (1H, m)

Reference Example 307 tert-Butyl{[5-(2-chlorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

By a similar operation as in Reference Example 301 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(300 mg), (2-chlorophenyl)boronic acid (218 mg),tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222mg), the title compound was obtained as a pale-blue oil (yield 171 mg,53%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.84 (3H, brs), 4.26 (2H, brs), 6.20(1H, d, J=1.8 Hz), 7.26-7.36 (6H, m), 7.65-7.71 (1H, m), 8.58-8.59 (1H,m), 8.75-8.79 (1H, m).

Reference Example 308 tert-Butyl{[5-(2,4-difluorophenyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

By a similar operation as in Reference Example 301 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(300 mg), (2,4-difluorophenyl)boronic acid (198 mg),tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (220mg), the title compound was obtained as a colorless oil (yield 113 mg,50%).

¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 2.84 (3H, brs), 4.30 (2H, brs), 6.49(1H, br), 6.78-6.92 (3H, m), 7.48-7.58 (1H, m), 8.78 (1H, br).

Reference Example 309 tert-Butyl{[5-(2,5-difluorophenyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

By a similar operation as in Reference Example 301 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(300 mg), (2,5-difluorophenyl)boronic acid (220 mg),tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (220mg), the title compound was obtained as a colorless oil (yield 135 mg,60%).

¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 2.84 (3H, brs), 4.30 (2H, brs), 6.56(1H, br), 6.77-6.85 (2H, m), 7.00-7.08 (1H, m), 7.20-7.26 (1H, m), 8.90(1H, br).

Reference Example 310 tert-Butyl{[5-(4-chloro-2-fluorophenyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

By a similar operation as in Reference Example 301 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(300 mg), (4-chloro-2-fluorophenyl)boronic acid (243 mg),tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (220mg), the title compound was obtained as a colorless oil (yield 127 mg,54%).

¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 2.84 (3H, s), 4.30 (2H, s), 6.55 (1H,br), 6.80 (1H, br), 7.11-7.15 (2H, m), 7.46-7.52 (1H, m), 8.82 (1H, br).

Reference Example 311 tert-Butyl{[5-(2,4-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

By a similar operation as in Reference Example 146 and using tert-butyl{[5-(2,4-difluorophenyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (113 mg),sodium hydride (60% in oil, 51 mg), 15-crown-5 (0.21 mL) andpyridin-3-ylsulfonyl chloride hydrochloride (113 mg), the title compoundwas obtained as a pale-yellow oil (yield 110 mg, 68%).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.82 (3H, brs), 4.24 (2H, brs), 6.19(1H, br), 6.77-6.92 (2H, m), 7.11-7.19 (1H, m), 7.33-7.37 (2H, m),7.68-7.72 (1H, m), 8.62 (1H, d, J=2.4 Hz), 8.77-8.79 (1H, m).

Reference Example 312 tert-Butyl{[5-(2,5-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

By a similar operation as in Reference Example 146 and using tert-butyl{[5-(2,5-difluorophenyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (135 mg),sodium hydride (60% in oil, 60 mg), 15-crown-5 (0.25 mL) andpyridin-3-ylsulfonyl chloride hydrochloride (135 mg), the title compoundwas obtained as a colorless oil (yield 105 mg, 54%).

¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 2.82 (3H, s), 4.23 (2H, brs), 6.24 (1H,br), 6.89-7.13 (4H, m), 7.33-7.39 (2H, m), 7.71-7.75 (1H, m), 8.67 (1H,d, J=2.4 Hz), 8.78-8.80 (1H, m).

Reference Example 313 tert-Butyl{[5-(4-chloro-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

By a similar operation as in Reference Example 146 and using tert-butyl{[5-(4-chloro-2-fluorophenyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (127mg), sodium hydride (60% in oil, 54 mg), 15-crown-5 (0.22 mL) andpyridin-3-ylsulfonyl chloride hydrochloride (120 mg), the title compoundwas obtained as a colorless oil (yield 103 mg, 57%).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.81 (3H, s), 4.23 (2H, brs), 6.21 (1H,brs), 7.08-7.15 (4H, m), 7.32-7.38 (2H, m), 7.69-7.73 (1H, m), 8.64 (1H,d, J=2.4 Hz), 8.77-8.79 (1H, m).

Reference Example 314 tert-Butyl{[5-(3-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

By a similar operation as in Reference Example 301 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(300 mg), (3-fluorophenyl)boronic acid (195 mg),tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222mg), the title compound was obtained as a pale-yellow oil (yield 280 mg,90%).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.81 (3H, brs), 4.22 (2H, brs), 6.16(1H, brs), 6.93-7.11 (3H, m), 7.27-7.32 (3H, m), 7.59-7.63 (1H, m), 8.58(1H, d, J=2.1 Hz), 8.73-8.75 (1H, m).

Reference Example 315 tert-Butyl{1-[5-bromo-2-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

5-Bromo-2-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (565mg) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL), a 40%solution (1.5 mL) of methylamine in methanol was added at roomtemperature and the mixture was stirred for 30 min. Sodium borohydride(130 mg) was added to the reaction mixture at room temperature and themixture was stirred for 15 min. The reaction mixture was concentratedunder reduced pressure, a saturated aqueous sodium hydrogencarbonatesolution was added to the residue, and the mixture was extracted withethyl acetate. The extract was washed with saturated aqueous sodiumhydrogencarbonate solution, water and saturated brine, dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was dissolved in ethyl acetate (6 mL),di-tert-butyl bicarbonate (0.45 mL) was added, and the mixture wasstirred at room temperature for 1 hr. To the reaction mixture was added1 mol/L hydrochloric acid (10 mL), and the mixture was further stirredfor 15 min. The reaction mixture was neutralized with saturated aqueoussodium hydrogencarbonate solution, and extracted with ethyl acetate. Theextract was washed with saturated aqueous sodium hydrogencarbonatesolution, water and saturated brine, dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1→1:1) to give a mixture of the title compoundand 5-bromo-2-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde.The mixture was dissolved in tetrahydrofuran (5 mL), a 2 mol/L solution(4 mL) of methylamine in tetrahydrofuran was added, and the mixture wasstirred at room temperature for 12 hr. To the reaction mixture was addeda solution of sodium borohydride (131 mg) in methanol (1 mL), and themixture was stirred for 1 hr. The reaction mixture was concentratedunder reduced pressure, a saturated aqueous sodium hydrogencarbonatesolution was added to the residue, and the mixture was extracted withethyl acetate. The extract was washed with saturated aqueous sodiumhydrogencarbonate solution, water and saturated brine, dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was dissolved in ethyl acetate (6 mL),di-tert-butyl bicarbonate (0.45 mL) was added, and the mixture wasstirred at room temperature for 1 hr. Saturated aqueous sodiumhydrogencarbonate solution was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed withsaturated aqueous sodium hydrogencarbonate solution, water and saturatedbrine, dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (developing solution: hexane-ethylacetate=2:1) to give the title compound as a yellow oil (yield 384 mg,50%).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.49 (3H, s), 2.71 (3H, brs), 4.15 (2H,brs), 6.24 (1H, brs), 7.47-7.52 (1H, m), 8.13-8.17 (1H, m), 8.84-8.86(1H, m), 9.07-9.08 (1H, m).

Reference Example 316N-({1-[(4-Methylphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)-1,1-diphenylmethanamine

A suspension (12 mL) of1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde (1.2 g),diphenylmethylamine (1.35 g) and powder molecular sieves 4A (5.0 g) indichloromethane was stirred at room temperature for 6 hr, sodiumtriacetoxyborohydride (1.56 g) was added, and the mixture was furtherstirred at room temperature for 3 hr. The reaction mixture was filteredthrough celite, and the filtrate was partitioned using an ethylacetate-saturated aqueous sodium hydrogencarbonate solution. The organiclayer was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=9:1→1:1). The obtained oil was left standing in a freezer(temperature: −20° C.) to give the title compound as a colorless solid(yield 1.61 g, 89%).

¹H-NMR (CDCl₃) δ: 2.34 (3H, s), 3.58 (2H, s), 4.82 (1H, s), 6.15 (1H, d,J=1.8 Hz), 7.09 (2H, d, J=8.8 Hz), 7.15-7.45 (18H, m).

Reference Example 3172,2,2-Trifluoro-N-({1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)acetamide

N-({1-[(4-Methylphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)-1,1-diphenylmethanamine(362 mg) was dissolved in ethyl acetate (3 mL), and methanol (5 mL) wasadded. 10% palladium carbon (50% water-containing product, 200 mg) and 1mol/L hydrochloric acid (0.73 mL) were added, and the mixture wasstirred under a hydrogen atmosphere at room temperature for 3 hr. Thereaction mixture was filtrated, and the filtrate was concentrated underreduced pressure. Saturated aqueous sodium hydrogencarbonate solutionwas added to the residue, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was dissolved in tetrahydrofuran (3 mL) and, after cooling to 0°C., triethylamine (0.203 mL) and trifluoroacetic anhydride (0.159 mL)were added. The reaction mixture was stirred at room temperature for 30min, concentrated under reduced pressure. Water was added to theresidue, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:1)to give the title compound as a colorless oil (yield 321 mg, 100%).

¹H-NMR (CDCl₃) δ: 2.36 (3H, s), 4.39 (2H, d, J=5.6 Hz), 6.10 (1H, d,J=2.2 Hz), 6.45 (1H, br), 7.05-7.45 (10H, m).

Example 1N-Methyl-1-{1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methanamine

To a solution (10 mL) of1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde (200 mg)in methanol were added methylammonium chloride (207 mg) and sodiumcyanoborohydride (39 mg), and the mixture was stirred at roomtemperature for 1 hr. Saturated aqueous sodium hydrogen carbonate wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by basic silica gel column chromatography (eluent:hexane-ethyl acetate=6:1→1:1) to give the title compound as a brown oil(yield 15 mg, 7%).

¹H-NMR (CDCl₃) δ: 2.35 (3H, s), 2.44 (3H, s), 3.59 (2H, s), 6.13 (1H, d,J=1.8 Hz), 7.08 (2H, d, J=8.0 Hz), 7.20-7.40 (9H, m).

Example 21-{1-[(4-Fluorophenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanamine

To a solution (5 mL) of1-[(4-fluorophenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde (160 mg)in tetrahydrofuran was added benzylmethylamine (88 mg), and the mixturewas stirred at room temperature for 30 min. Sodium triacetoxyborohydride(329 mg) was added to the reaction mixture, and the mixture was stirredat room temperature for 1 hr. Saturated aqueous sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue wasdissolved in methanol (5 mL), 10% palladium carbon (50% water-containingproduct, 180 mg) and formic acid (0.027 mL) were added, and the mixturewas stirred under a hydrogen atmosphere at room temperature for 10 hr.The reaction mixture was filtrated, and the filtrate was concentratedunder reduced pressure. To the residue was added saturated aqueoussodium hydrogen carbonate, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by basic silica gel column chromatography (eluent:hexane-ethyl acetate=6:1→2:1) to give the title compound as a colorlessoil (yield 55 mg, 33%).

¹H-NMR (CDCl₃) δ: 2.45 (3H, s), 3.60 (2H, s), 6.16 (1H, d, J=1.8 Hz),6.96 (2H, t, J=8.8 Hz), 7.20-7.40 (9H, m).

Example 31-[1-(Methylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]-N-methylmethanamine

To a solution (5 mL) of1-(methylsulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde (160 mg) intetrahydrofuran was added benzylmethylamine (117 mg), and the mixturewas stirred at room temperature for 30 min. Sodium triacetoxyborohydride(435 mg) was added to the reaction mixture, and the mixture was stirredat room temperature for 1 hr. Saturated aqueous sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue wasdissolved in methanol (10 mL), 10% palladium carbon (50%water-containing product, 200 mg) and 1 mol/l hydrochloric acid (1 mL)were added, and the mixture was stirred under a hydrogen atmosphere atroom temperature for 18 hr. The reaction mixture was filtrated; and thefiltrate was concentrated under reduced pressure. Saturated aqueoussodium hydrogen carbonate was added to the residue, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by basic silica gel columnchromatography (eluent: hexane-ethyl acetate=6:1→ethyl acetate) to givethe title compound as a colorless oil (yield 62 mg, 37%).

¹H-NMR (CDCl₃) δ: 2.50 (3H, s), 2.82 (3H, s), 3.64 (2H, s), 6.31 (1H, d,J=1.8 Hz), 7.21 (1H, d, J=1.8 Hz), 7.38-7.40 (3H, m), 7.45-7.55 (2H, m).

Example 41-{1-[(4-Methoxyphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanaminehydrochloride

1-[(4-Methoxyphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde (240mg) was dissolved in methanol (5 mL), methylammonium chloride (856 mg)and sodium cyanoborohydride (131 mg) were added, and the mixture wasstirred at room temperature for 18 hr. The reaction mixture wasconcentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue; and the mixture was extracted withethyl acetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by basic silica gel column chromatography (eluent:hexane-ethyl acetate=6:1→ethyl acetate). The obtained oil was dissolvedin ethyl acetate (5 mL), 4 mol/L hydrogen chloride-ethyl acetatesolution (0.5 mL) was added, and the mixture was concentrated underreduced pressure. The residue was recrystallized from ethyl acetate togive the title compound as colorless crystals (yield 148 mg, 54%).

¹H-NMR (CDCl₃) δ: 2.56 (3H, s), 3.80 (3H, s), 3.98 (2H, s), 6.45 (1H, d,J=2.2 Hz), 6.74 (2H, d, J=7.0 Hz), 7.10-7.40 (7H, m), 7.64 (1H, d, J=2.2Hz), 9.82 (2H, br).

Example 51-{1-[(4-Fluorophenyl)sulfonyl]-2-methyl-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanaminehydrochloride

To a solution (5 mL) of1-[(4-fluorophenyl)sulfonyl]-2-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde(205 mg) in tetrahydrofuran was added benzylmethylamine (108 mg), andthe mixture was stirred at room temperature for 30 min. To the reactionmixture was added sodium triacetoxyborohydride (303 mg), and the mixturewas stirred at room temperature for 1 hr. Saturated aqueous sodiumhydrogen carbonate was added, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was dissolved in methanol (10 mL), 10% palladium carbon (50%water-containing product, 100 mg) and 1 mol/l hydrochloric acid (0.60mL) were added, and the mixture was stirred under a hydrogen atmosphereat room temperature for 2 hr. 10% palladium carbon (50% water-containingproduct, 200 mg) was added, and the mixture was stirred under a hydrogenatmosphere at room temperature for 18 hr. The reaction mixture wasfiltrated, and the filtrate was concentrated under reduced pressure.Saturated aqueous sodium hydrogen carbonate was added to the residue,and the mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was dissolved in ethylacetate (5 mL), 4 mol/L hydrogen chloride-ethyl acetate (0.5 mL) wasadded, and the mixture was concentrated under reduced pressure to givethe title compound as a colorless amorphous solid (yield 100 mg, 42%).

¹H-NMR (CDCl₃) δ: 2.45 (3H, s), 2.56 (3H, s), 3.89 (2H, s), 6.42 (1H,s), 7.03 (2H, t, J=8.1 Hz), 7.15-7.45 (7H, m), 9.00-10.00 (2H, br).

Example 61-{5-(4-Fluorophenyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine

5-(4-Fluorophenyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole-3-carbaldehyde(0.49 g) was dissolved in methanol (12 mL), and methylammonium chloride(1.17 g) and sodium cyanoborohydride (0.27 g) were added. After stirringat room temperature for 18 hr, the mixture was concentrated underreduced pressure. The residue was dissolved in water, and the solutionwas alkalized with a saturated aqueous sodium hydrogencarbonate solutionand extracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: ethyl acetate-methanol=5:1) to givethe title compound as a colorless solid (yield 0.42 g, 82%).

¹H-NMR (CDCl₃) δ: 2.36 (3H, s), 2.45 (3H, s), 3.60 (2H, s), 6.13 (1H, d,J=2.1 Hz), 6.98 (2H, t, J=8.8 Hz), 7.09-7.13 (2H, m), 7.17-7.27 (5H, m),7.33 (1H, s).

Example 7N-Methyl-1-{5-(3-methylphenyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrol-3-yl}methanaminehydrochloride

Using5-(3-methylphenyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole-3-carbaldehyde(0.36 g), methylammonium chloride (0.89 g) and sodium cyanoborohydride(0.21 g), a procedure as in Example 4 was performed to give the titlecompound as white crystals (yield 0.22 g, 52%).

¹H-NMR (DMSO-d₆) δ: 2.26 (3H, s), 2.36 (3H, s), 3.33 (3H, s), 3.96 (2H,s), 6.38 (1H, d, J=1.8 Hz), 6.79 (1H, s), 6.84-6.99 (1H, m), 7.22-7.34(6H, m), 7.69 (1H, d, J=2.1 Hz), 8.98 (2H, brs).

Example 8N-Methyl-1-{5-(3-fluorophenyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrol-3-yl}methanaminehydrochloride

Using5-(3-fluorophenyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole-3-carbaldehyde(0.57 g), methylammonium chloride (1.38 g) and sodium cyanoborohydride(0.32 g), a procedure as in Example 4 was performed to give the titlecompound as white crystals (yield 0.45 g, 69%).

¹H-NMR (DMSO-d₆) δ: 2.36 (3H, s), 3.32 (3H, s), 3.98 (2H, s), 6.48 (1H,d, J=1.8 Hz), 6.94-7.00 (2H, m), 7.25-7.45 (6H, m), 7.73 (1H, d, J=1.8Hz), 8.94 (2H, brs).

Example 9N-Methyl-1-{1-[(2-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methanaminehydrochloride

1-[(2-Methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde (390 mg)was dissolved in methanol (10 mL), 40% methylamine methanol solution(280 mg) was added at room temperature and the mixture was stirred for15 min. To the reaction mixture was added sodium borohydride (70 mg) atroom temperature and the mixture was stirred for 10 min. Thereto wasadded 1 mol/l hydrochloric acid (10 mL), and the mixture was stirred for5 min. The mixture was alkalized with a saturated aqueous sodiumhydrogen carbonate and extracted with ethyl acetate. The extract waswashed with saturated brine, dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by basic silica gel column chromatography (eluent: hexane-ethylacetate=50:50→0:100), and the obtained oil was dissolved in ethylacetate (5 mL). 4 mol/l Hydrochloric acid-ethyl acetate (1 mL) was addedand the mixture was concentrated under reduced pressure. The residue wascrystallized from ethyl acetate to give the title compound as colorlesscrystals (yield 342 mg, 76%).

¹H-NMR (DMSO-d₆) δ: 2.21 (3H, s), 2.52-2.54 (3H, m), 4.02 (2H, s),6.48-6.50 (1H, m), 6.99-7.01 (2H, m), 7.07-7.13 (2H, m), 7.20-7.23 (2H,m), 7.30-7.37 (2H, m), 7.50-7.54 (1H, m), 7.79 (1H, br), 9.13 (2H, br).

Example 10N-Methyl-1-(5-phenyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrol-3-yl)methanaminehydrochloride

Using5-phenyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrole-3-carbaldehyde(65 mg), 40% methylamine methanol solution (50 mg) and sodiumborohydride (24 mg), a procedure as in Example 9 was performed to givethe title compound as colorless crystals (yield 50 mg, 68%).

¹H-NMR (DMSO-d₆) δ: 2.50-2.51 (3H, m), 3.99 (2H, s), 6.48 (1H, s),7.13-7.15 (2H, m), 7.35-7.38 (2H, m), 7.42-7.46 (1H, m), 7.61 (2H, d,J=8.3 Hz), 7.78-7.78 (1H, m), 7.92 (2H, d, J=8.5 Hz), 9.03 (2H, br).

Example 111-{1-[(4-Fluoro-2-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanaminehydrochloride

Using1-[(4-fluoro-2-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde(165 mg), 40% methylamine methanol solution (112 mg) and sodiumborohydride (28 mg), a procedure as in Example 9 was performed to givethe title compound as colorless crystals (yield 106 mg, 56%).

¹H-NMR (DMSO-d₆) δ: 2.19 (3H, s), 2.53 (3H, s), 4.02 (2H, s), 6.49 (1H,d, J=1.7 Hz), 6.90-6.95 (1H, m), 7.00-7.02 (2H, m), 7.18 (1H, dd, J=9.0Hz, 5.6 Hz), 7.23-7.26 (2H, m), 7.30 (1H, dd, J=9.9 Hz, 2.6 Hz),7.32-7.36 (1H, m), 7.79 (1H, s), 9.15 (2H, br).

Example 12N,N-Dimethyl-1-(5-phenyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrol-3-yl)methanaminehydrochloride

Using5-phenyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrole-3-carbaldehyde(80 mg), 2 mol/l dimethylamine-tetrahydrofuran solution (1 mL) andsodium borohydride (24 mg), a procedure as in Example 9 was performed togive the title compound as colorless crystals (yield 59 mg, 63%).

¹H-NMR (DMSO-d₆) δ: 2.67 (6H, s), 4.12 (2H, s), 6.56-6.56 (1H, m),7.15-7.17 (2H, m), 7.34-7.38 (2H, m), 7.42-7.46 (1H, m), 7.63 (2H, d,J=8.3 Hz), 7.85 (1H, d, J=1.7 Hz), 7.92 (2H, d, J=8.3 Hz), 10.68 (1H,br).

Example 131-[5-(4-Fluorophenyl)-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

Using 1-(4-phenylsulfonyl)-5-(4-fluorophenyl)-1H-pyrrole-3-carbaldehyde(0.60 g), methylammonium chloride (1.48 g) and sodium cyanoborohydride(0.33 g), a procedure as in Example 4 was performed to give the titlecompound as colorless crystals (yield 0.35 g, 51%).

¹H-NMR (DMSO-d₆) δ: 2.52 (3H, s), 3.98 (2H, t, J=8.7 Hz), 6.43 (1H, s),7.12-7.23 (4H, m), 7.40 (2H, d, J=7.35 Hz), 7.53 (2H, t, J=7.9 Hz),7.68-7.74 (2H, m), 8.96 (2H, br).

Example 14N-Methyl-1-[5-(2-methylphenyl)-1-(4-methylphenylsulfonyl)-1H-pyrrol-3-yl]methanaminehydrochloride

Using5-(2-methylphenyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole-3-carbaldehyde(0.46 g), methylammonium chloride (1.11 g) and sodium cyanoborohydride(0.26 g), a procedure as in Example 4 was performed to give the titlecompound as colorless crystals (yield 0.37 g, 80%).

¹H-NMR (DMSO-d₆) δ: 1.79 (3H, s), 2.38 (3H, s), 3.32 (3H, s), 4.00 (2H,s), 6.34 (1H, d, J=1.8 Hz), 6.84 (1H, d, J=6.2 Hz), 7.11-7.21 (2H, m),7.25-7.36 (6H, m), 7.72 (1H, s), 9.02 (1H, brs).

Example 151-{5-(4-Fluorophenyl)-1-[(4-fluorophenyl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine

Using5-(4-fluorophenyl)-1-[(4-fluorophenyl)sulfonyl]-1H-pyrrole-3-carbaldehyde(0.52 g), methylammonium chloride (1.20 g) and sodium cyanoborohydride(0.28 g), a procedure as in Example 6 was performed to give the titlecompound as a colorless oil (yield 0.39 g, 72%).

¹H-NMR (CDCl₃) δ: 1.55 (1H.brs), 2.45 (3H, s), 3.59 (2H, s), 6.14 (1H,d, J=1.9 Hz), 6.96-7.04 (4H, m), 7.17-7.23 (2H, m), 7.31-7.38 (3H, m).

Example 161-(5-(4-Fluorophenyl)-1-{[4-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrol-3-yl)-N-methylmethanamine

To a solution (12 mL) of5-(4-fluorophenyl)-1-{[4-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrole-3-carbaldehyde(0.55 g) in methanol were added methylammonium chloride (1.11 g) andsodium cyanoborohydride (0.26 g), and the mixture was stirred at roomtemperature for 18 hr. The reaction mixture was concentrated underreduced pressure, saturated aqueous sodium hydrogen carbonate was added,and the mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by basicsilica gel column chromatography (eluent: hexane-ethyl acetate=1:1) togive the title compound as colorless crystals (yield 0.39 g, 68%).

¹H-NMR (CDCl₃) δ: 1.49 (1H, brs), 2.44 (3H, s), 3.60 (2H, s), 6.17 (1H,d, J=1.7 Hz), 7.01 (2H, t, J=8.7 Hz), 7.20 (2H, dd, J=8.8 Hz, 5.4 Hz),7.34 (1H, d, J=0.94 Hz), 7.47 (2H, d, J=8.3 Hz), 7.60 (2H, d, J=8.3 Hz).

Example 171-[1-[(4-Fluorophenyl)sulfonyl]-5-(4-methoxyphenyl)-1H-pyrrol-3-yl]-N-methylmethanamine

Using1-(4-fluorophenylsulfonyl)-5-(4-methoxyphenyl)-1H-pyrrole-3-carbaldehyde(0.28 g), methylammonium chloride (0.62 g) and sodium cyanoborohydride(0.15 g), a procedure as in Example 6 was performed to give the titlecompound as a colorless oil (yield 0.13 g, 44%).

¹H-NMR (CDCl₃) δ: 1.52 (1H, brs), 2.45 (3H, s), 3.59 (2H, s), 3.85 (3H,s), 6.10 (1H, s), 6.84 (2H, d, J=8.9 Hz), 6.92-7.02 (2H, m), 7.14 (2H,d, J=8.9 Hz), 7.29-7.38 (3H, m).

Example 181-{1-[(4-Fluorophenyl)sulfonyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrol-3-yl}-N-methylmethanaminehydrochloride

Using1-[(4-fluorophenyl)sulfonyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbaldehyde(0.55 g), methylammonium chloride (1.17 g) and sodium cyanoborohydride(0.27 g), a procedure as in Example 4 was performed to give the titlecompound as a colorless crystal (yield 0.33 g, 53%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 3.33 (2H, s), 6.48 (1H, s), 7.17 (1H,d, J=8.3 Hz), 7.43 (2H, d, J=8.9 Hz), 7.51-7.59 (2H, m), 7.65-7.74 (2H,m), 7.76-7.81 (2H, m), 9.04 (2H, brs).

Example 19N-Methyl-1-{1-(4-methylphenyl)sulfonyl}-5-[2-(trifluoromethyl)phenyl]-1H-pyrrol-3-yl}methanaminehydrochloride

Using1-[(4-methylphenyl)sulfonyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbaldehyde(0.28 g), methylammonium chloride (0.58 g) and sodium cyanoborohydride(0.14 g), a procedure as in Example 4 was performed to give the titlecompound as colorless crystals (yield 0.11 g, 35%).

¹H-NMR (DMSO-d₆) δ: 2.39 (3H, s), 2.50 (3H, s), 3.32 (2H, s), 6.43 (1H,s), 7.12 (1H, d, J=6.8 Hz), 7.37 (4H, s), 7.63-7.79 (4H, m), 8.92 (2H,brs).

Example 20N-Methyl-1-[2-methyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanaminehydrochloride

Using 2-methyl-5-phenyl-1-phenylsulfonyl-1H-pyrrole-3-carbaldehyde (0.27g), methylammonium chloride (0.68 g) and sodium cyanoborohydride (0.28g), a procedure as in Example 4 was performed to give the title compoundas colorless crystals (yield 0.11 g, 35%).

¹H-NMR (DMSO-d₆) δ: 2.44 (3H, s), 2.50 (3H, s), 3.91 (2H, s), 6.40 (1H,s), 7.22-7.28 (2H, m), 7.34-7.49 (5H, m), 7.57 (2H, t, J=7.8 Hz), 7.72(1H, t, J=6.8 Hz), 8.84 (2H, brs).

Example 211-{5-(2,4-Difluorophenyl)-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanaminehydrochloride

tert-Butyl({5-bromo-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate(150 mg) was dissolved in a mixture of 1,2-dimethoxyethane (5 mL) anddistilled water (5 mL), and (2,4-difluorophenyl)boronic acid (103 mg)and sodium carbonate (104 mg) were added. After nitrogen substitution,tetrakis(triphenylphosphine)palladium (57 mg) was added, and the mixturewas stirred under a nitrogen atmosphere at 105° C. for 5 hr. Thereaction mixture was filtrated, water was added to the filtrate and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was dissolved in trifluoroaceticacid (5 mL), and the mixture was stirred at room temperature for 10 min,and concentrated under reduced pressure. Saturated aqueous sodiumhydrogen carbonate was added to the residue, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by basic silica gel columnchromatography (eluent: hexane-ethyl acetate=9:1→1:1), and the obtainedoil was dissolved in ethyl acetate (5 mL), 4 mol/L hydrogenchloride-ethyl acetate solution (0.5 mL) was added, and the mixture wasconcentrated under reduced pressure. The residue was recrystallized fromethyl acetate to give the title compound as pale-red crystals (yield 58mg, 41%).

¹H-NMR (CDCl₃) δ: 2.56 (3H, t, J=5.2 Hz), 3.83 (3H, s), 3.98 (2H, brs),6.54 (1H, d, J=1.6 Hz), 6.70-6.90 (4H, m), 7.00-7.20 (1H, m), 7.38 (2H,d, J=9.0 Hz), 6.78 (1H, d, J=1.6 Hz), 9.85 (2H, br).

Example 221-[1-[(4-Methoxyphenyl)sulfonyl]-5-(4-phenoxyphenyl)-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

Using tert-butyl({5-bromo-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate(150 mg), (4-phenoxyphenyl)boronic acid (140 mg), sodium carbonate (104mg) and tetrakis(triphenylphosphine)palladium (57 mg), a procedure as inExample 21 was performed to give the title compound as pale-yellowcrystals (yield 88 mg, 55%).

¹H-NMR (CDCl₃) δ: 2.57 (3H, s), 3.80 (3H, s), 3.98 (2H, s), 6.46 (1H, d,J=2.2 Hz), 6.77 (2H, d, J=9.2 Hz), 6.88 (2H, d, J=8.8 Hz), 7.00-7.20(5H, m), 7.25-7.45 (4H, m), 7.62 (1H, d, J=2.2 Hz), 9.85 (2H, br).

Example 231-[1-[(4-Methoxyphenyl)sulfonyl]-5-(2-naphthyl)-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

Using tert-butyl({5-bromo-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate(150 mg), 2-naphthylboronic acid (112 mg), sodium carbonate (104 mg) andtetrakis(triphenylphosphine)palladium (57 mg), a procedure as in Example21 was performed to give the title compound as pale-blue crystals (yield64 mg, 44%).

¹H-NMR (DMSO-d₆) δ: 3.33 (3H, s), 3.79 (3H, s), 4.00 (2H, s), 6.52 (1H,s), 6.95 (2H, d, J=8.8 Hz), 7.30-7.40 (3H, m), 7.50-7.70 (3H, m), 7.75(1H, s), 7.80-8.00 (3H, m), 9.02 (2H, br).

Example 243-{1-[(4-Methoxyphenyl)sulfonyl]-4-[(methylamino)methyl]-1H-pyrrol-2-yl}anilinedihydrochloride

Using tert-butyl({5-bromo-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate(150 mg), (3-aminophenyl)boronic acid (122 mg), sodium carbonate (104mg) and tetrakis(triphenylphosphine)palladium (57 mg), a procedure as inExample 21 was performed to give the title compound as colorlesscrystals (yield 45 mg, 31%).

¹H-NMR (DMSO-d₆) δ: 2.51 (3H, s), 3.83 (3H, s), 3.96 (2H, s), 6.46 (1H,s), 6.90-7.15 (4H, m), 7.20-7.30 (1H, m), 7.30-7.45 (3H, m), 7.71 (1H,s), 9.11 (2H, br).

Example 251-{1-[(4-Methoxyphenyl)sulfonyl]-5-pyridin-3-yl-1H-pyrrol-3-yl}-N-methylmethanaminedihydrochloride

Using tert-butyl({5-bromo-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate(150 mg), pyridin-3-ylboronic acid (96 mg), sodium carbonate (104 mg)and tetrakis(triphenylphosphine)palladium (57 mg), a procedure as inExample 21 was performed to give the title compound as pale-yellowcrystals (yield 16 mg, 11%).

¹H-NMR (DMSO-d₆) δ: 2.51 (3H, s), 3.82 (3H, s), 3.98 (2H, s), 6.65 (1H,d, J=1.4 Hz), 7.03 (2H, d, J=8.8 Hz), 7.38 (2H, d, J=8.8 Hz), 7.68 (1H,m), 7.82 (1H, d, J=1.4 Hz), 7.92 (1H, d, J=9.2 Hz), 8.50 (1H, s), 8.73(1H, d, J=4.8 Hz), 9.21 (2H, br).

Example 261-{1-[(4-Methylphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methanaminehydrochloride

To a solution (10 mL) of4-(azidomethyl)-1-[(4-methylphenyl)sulfonyl]-2-phenyl-1H-pyrrole (230mg) in methanol was added 10% palladium carbon (50% water-containingproduct, 150 mg), and the mixture was stirred under a hydrogenatmosphere at room temperature for 18 hr. To the reaction mixture wasadded acetic acid (1 mL), and the mixture was stirred under a hydrogenatmosphere at room temperature for 18 hr. The reaction mixture wasfiltrated, saturated aqueous sodium hydrogen carbonate was added to thefiltrate, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was purified bybasic silica gel column chromatography (eluent: hexane-ethylacetate=9:1→ethyl acetate), and the obtained oil was dissolved in ethylacetate (5 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (0.5mL) was added, and the mixture was concentrated under reduced pressure.The residue was recrystallized from ethyl acetate to give the titlecompound as colorless crystals (yield 10 mg, 4%).

¹H-NMR (DMSO-d₆) δ: 2.35 (3H, s), 3.89 (2H, s), 6.39 (1H, d, J=1.8 Hz),7.10-7.20 (2H, m), 7.22-7.50 (7H, m), 7.66 (1H, d, J=1.8 Hz), 8.20 (3H,br).

Example 27N-Methyl-1-{4-methyl-1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methanaminehydrochloride

Using4-methyl-1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde(310 mg), methylammonium chloride (617 mg) and sodium cyanoborohydride(172 mg), a procedure as in Example 4 was performed to give the titlecompound as colorless crystals (yield 179 mg, 50%).

¹H-NMR (DMSO-d₆) δ: 1.77 (3H, s), 2.36 (3H, s), 2.55 (3H, s), 3.96 (2H,s), 7.00 (2H, dd, J=1.8 Hz, 8.0 Hz), 7.20-7.50 (7H, m), 7.73 (1H, s),9.06 (2H, br).

Example 283-{4-[(Methylamino)methyl]-1-[(4-methylphenyl)sulfonyl]-1H-pyrrol-2-yl}benzonitrilehydrochloride

Using tert-butyl({5-bromo-1-[(4-methylphenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate(250 mg), (3-cyanophenyl)boronic acid (103 mg), sodium carbonate (83 mg)and tetrakis(triphenylphosphine)palladium (65 mg), a procedure as inExample 21 was performed to give the title compound as pale-bluecrystals (yield 96 mg, 43%).

¹H-NMR (DMSO-d₆) δ: 2.37 (3H, s), 2.51 (3H, s), 3.98 (2H, s), 6.56 (1H,d, J=1.8 Hz), 7.20-7.40 (4H, m), 7.50-7.65 (3H, m), 7.77 (1H, d, J=1.8Hz), 7.90 (1H, d, J=7.6 Hz), 9.11 (2H, br).

Example 294-{4-[(Methylamino)methyl]-1-[(4-methylphenyl)sulfonyl]-1H-pyrrol-2-yl}benzonitrilehydrochloride

Using tert-butyl({5-bromo-1-[(4-methylphenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate(250 mg), (4-cyanophenyl)boronic acid (103 mg), sodium carbonate (83 mg)and tetrakis(triphenylphosphine)palladium (65 mg), a procedure as inExample 21 was performed to give the title compound as pale-bluecrystals (yield 75 mg, 33%).

¹H-NMR (DMSO-d₆) δ: 2.36 (3H, s), 2.51 (3H, s), 3.97 (2H, s), 6.59 (1H,d, J=1.8 Hz), 7.34 (4H, m), 7.38 (2H, d, J=8.4 Hz), 7.79 (1H, d, J=1.8Hz), 7.86 (2H, d, J=8.4 Hz), 9.11 (2H, br).

Example 30N-methyl-1-[1-(phenylsulfonyl)-5-(3-thienyl)-1H-pyrrol-3-yl]methanaminehydrochloride

To a solution of tert-butylmethyl{[1-(phenylsulfonyl)-5-(3-thienyl)-1H-pyrrol-3-yl]methyl}carbamate(0.62 g) in methanol (10 mL) was added 4 mol/L hydrogen chloride-ethylacetate solution (6 mL), and the mixture was stirred at room temperaturefor 3 hr. Activated carbon was added to the reaction mixture, themixture was filtrated, and the filtrate was concentrated under reducedpressure. The residue was recrystallized from ethanol to give the titlecompound as a colorless solid (yield 0.38 g, 71%).

¹H-NMR (CDCl₃) δ: 2.55 (3H, s), 3.96 (2H, s), 6.54 (1H, d, J=1.8 Hz),6.98 (1H, dd, J=1.2, 5.1 Hz), 7.09 (1H, dd, J=1.2, 3.0 Hz), 7.21 (1H,dd, J=3.0, 5.1 Hz), 7.31-7.42 (4H, m), 7.48-7.54 (1H, m), 7.65 (1H, d,J=1.8 Hz), 9.84 (2H, brs).

Example 31N-Methyl-1-[5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanaminehydrochloride

Using tert-butylmethyl{[5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate(0.64 g), a procedure as in Example 30 was performed to give the titlecompound as a colorless solid (yield 0.39 g, 73%).

¹H-NMR (CDCl₃) δ: 2.55 (3H, s), 3.98 (2H, s), 6.47 (1H, d, J=1.8 Hz),7.12-7.15 (2H, m), 7.23-7.37 (7H, m), 7.47-7.53 (1H, m), 7.65 (1H, d,J=1.8 Hz), 9.83 (2H, brs).

Example 321-{1-[(4-Fluorophenyl)sulfonyl]-5-(3-thienyl)-1H-pyrrol-3-yl}-N-methylmethanaminehydrochloride

Using tert-butyl{{1-[(4-fluorophenyl)sulfonyl]-5-(3-thienyl)-1H-pyrrol-3-yl}methyl}methylcarbamate(0.44 g), a procedure as in Example 30 was performed to give the titlecompound as a colorless solid (yield 92 mg, 32%).

¹H-NMR (CDCl₃) δ: 2.56-2.60 (3H, m), 3.96-3.98 (2H, m), 6.53 (1H, d,J=2.1 Hz), 6.98-7.04 (3H, m), 7.12-7.14 (1H, m), 7.23-7.26 (1H, m),7.38-7.44 (2H, m), 7.66 (1H, d, J=2.1 Hz), 9.85 (2H, brs).

Example 331-{1-[(3-Chlorophenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanaminehydrochloride tert-Butyl{{1-[(3-chlorophenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl}methylcarbamate(726 mg) was dissolved in dichloromethane (3 ml), trifluoroacetic acid(2 ml) was added at 0° C., and the mixture was stirred at roomtemperature for 15 min. The reaction solution was basified by thedropwise addition to 6% aqueous sodium hydrogencarbonate solution, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was subjected to basicsilica gel column chromatography, and eluted with ethyl acetate-methanol(19:1). The obtained pale-yellow oil was dissolved in ethyl acetate, 4mol/L hydrogen chloride-ethyl acetate solution was added, activatedcarbon was added and the mixture was filtered through celite. The celitewas washed sufficiently with methanol and the filtrate was concentratedunder reduced pressure. The residue was crystallized from ethyl acetateand hexane, and recrystallized from ethyl acetate-ethanol to give thetitle compound as colorless crystals (yield 324 mg, 52%).

¹H-NMR (CDCl₃) δ: 1.64 (1H, br), 2.57 (3H, s), 3.99 (1H, s), 6.50 (1H,s), 7.12-7.49 (9H, m), 7.64 (1H, s), 9.85 (1H, br).

Example 341-[1-[(3-Chlorophenyl)sulfonyl]-5-(3-thienyl)-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

Using tert-butyl{[1-[(3-chlorophenyl)sulfonyl]-5-(3-thienyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(712 mg), a procedure as in Example 33 was performed to give the titlecompound as colorless crystals (yield 388 mg, 63%).

¹H-NMR (CDCl₃) δ: 1.75 (1H, br), 2.58 (3H, s), 3.97 (2H, s), 6.56 (1H,d, J=2.1 Hz), 6.97-6.99 (1H, m), 7.12-7.14 (1H, m), 7.24-7.31 (4H, m),7.45-7.49 (1H, m), 7.64 (1H, d, J=2.1 Hz), 9.80 (1H, br).

Example 351-[1-[(3-Chlorophenyl)sulfonyl]-5-(4-fluorophenyl)-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

Using tert-butyl{[1-[(3-chlorophenyl)sulfonyl]-5-(4-fluorophenyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(930 mg), a procedure as in Example 33 was performed to give the titlecompound as colorless crystals (yield 50 mg, 6%).

¹H-NMR (CDCl₃) δ: 2.58 (3H, s), 3.98 (2H, s), 6.50 (1H, d, J=1.8 Hz),6.96-7.02 (2H, m), 7.10-7.15 (2H, m), 7.22-7.24 (1H, m), 7.29-7.31 (2H,m), 7.47-7.51 (1H, m), 7.63-7.64 (1H, m), 9.80 (2H, br).

Example 361-{1-[(4-Chlorophenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanaminehydrochloride

To a solution (7 mL) of tert-butylmethyl[(5-phenyl-1H-pyrrol-3-yl)methyl]carbamate (70 mg) inN,N-dimethylformamide was added sodium hydride (60% in oil, 13 mg) andthe mixture was stirred for 30 min. 4-Chlorobenzenesulfonyl chloride (62mg) was added at room temperature and the mixture was stirred for 1 hr.To the reaction mixture was added ice water, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=19:1→4:1), and dissolved inmethanol (10 mL). 4 mol/L Hydrogen chloride-ethyl acetate solution (1.5mL) was added and the mixture was stirred at 65° C. for 30 min. Thereaction mixture was concentrated under reduced pressure, andcrystallized from ethyl acetate to give the title compound as pale-redcrystals (yield 39 mg, 40%).

¹H-NMR (DMSO-d₆) δ: 2.51 (3H, s), 3.98 (2H, s), 6.47 (1H, d, J=1.8 Hz),7.14-7.16 (2H, m), 7.36-7.46 (5H, m), 7.59-7.63 (2H, m), 7.74 (1H, d,J=1.8 Hz), 9.03 (2H, br).

Example 371-{1-[(3,4-Difluorophenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanaminehydrochloride

To a solution (7 mL) of tert-butylmethyl[(5-phenyl-1H-pyrrol-3-yl)methyl]carbamate (70 mg) intetrahydrofuran was added tert-butoxy potassium (42 mg) at roomtemperature and the mixture was stirred for 30 min.3,4-Difluorobenzenesulfonyl chloride (68 mg) was added at roomtemperature and the mixture was stirred for 1.5 hr. To the reactionmixture was added ice water, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→4:1), and dissolved in methanol (15 mL). 4mol/l Hydrogen chloride-ethyl acetate solution (1.5 mL) was added andthe mixture was stirred at 65° C. for 30 min. The reaction mixture wasconcentrated under reduced pressure, and crystallized from ethyl acetateto give the title compound as pale-brown crystals (yield 32 mg, 33%).

¹H-NMR (DMSO-d₆) δ: 2.53 (3H, s), 3.99 (2H, s), 6.47 (1H, d, J=1.8 Hz),7.14-7.17 (2H, m), 7.25-7.30 (1H, m), 7.36-7.48 (4H, m), 7.60-7.69 (1H,m), 7.74 (1H, d, J=1.8 Hz), 8.98 (2H, br).

Example 381-[1-(2,3-Dihydro-1-benzofuran-5-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]-N-methylmethanamine0.5 oxalic acid salt

To a solution (5 mL) of tert-butylmethyl[(5-phenyl-1H-pyrrol-3-yl)methyl]carbamate (28 mg) inN,N-dimethylformamide was added sodium hydride (60% in oil, 40 mg) atroom temperature and the mixture was stirred for 30 min.2,3-Dihydro-1-benzofuran-5-sulfonyl chloride (65 mg) was added at roomtemperature and the mixture was stirred for 1 hr. To the reactionmixture was added ice water, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→4:1), and dissolved in methanol (10 mL). 4mol/l Hydrogen chloride-ethyl acetate solution (1.5 mL) was added andthe mixture was stirred at 65° C. for 30 min. The reaction mixture wasconcentrated under reduced pressure to give a free form, which wascrystallized from ethyl acetate as a 0.5 oxalic acid salt to give thetitle compound as pale-red crystals (yield 26 mg, 63%).

¹H-NMR (DMSO-d₆) δ: 2.53 (3H, s), 3.11 (2H, d, J=8.8 Hz), 3.98 (2H, s),4.64 (2H, d, J=8.8 Hz), 6.34 (1H, d, J=1.7 Hz), 6.80-6.83 (1H, m),7.12-7.15 (4H, m), 7.34-7.46 (3H, m), 7.64 (1H, d, J=1.7 Hz).

Example 391-[1-(Butylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]-N-methylmethanamine 0.5oxalic acid salt

Using tert-butyl methyl[(5-phenyl-1H-pyrrol-3-yl)methyl]carbamate (70mg), sodium hydride (60% in oil, 98 mg) and butane-1-sulfonyl chloride(230 mg), a procedure as in Example 38 was performed to give the titlecompound as pale-purplish red crystals (yield 18 mg, 21%).

¹H-NMR (DMSO-d₆) δ: 0.75 (3H, t, J=7.2 Hz), 1.14-1.38 (4H, m), 2.56 (3H,s), 3.21 (2H, t, J=7.2 Hz), 4.01 (2H, s), 6.48 (1H, s), 7.44 (5H, br),7.48 (1H, s).

Example 401-{1-[(4-Isopropoxyphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanamine0.5 oxalic acid salt

Using tert-butyl methyl[(5-phenyl-1H-pyrrol-3-yl)methyl]carbamate (70mg), sodium hydride (60% in oil, 98 mg) and 4-isopropoxybenzenesulfonylchloride (201 mg), a procedure as in Example 38 was performed to givethe title compound as pale-red crystals (yield 47 mg, 45%).

¹H-NMR (DMSO-d₆) δ: 1.26 (6H, d, J=6.0 Hz), 2.52 (3H, s), 3.98 (2H, s),4.66-4.74 (1H, m), 6.35 (1H, d, J=1.7 Hz), 6.96 (2H, d, J=9.0 Hz),7.14-7.16 (2H, m), 7.27 (2H, d, J=9.0 Hz), 7.32-7.45 (3H, m), 7.66 (1H,d, J=1.7 Hz).

Example 411-{1-[(3-Methoxyphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanaminehydrochloride

Using tert-butyl methyl[(5-phenyl-1H-pyrrol-3-yl)methyl]carbamate (200mg), sodium hydride (60% in oil, 140 mg) and 3-methoxybenzenesulfonylchloride (433 mg), a procedure as in Example 36 was performed to givethe title compound as pale-purple crystals (yield 186 mg, 68%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 3.68 (3H, s), 3.97 (2H, s), 6.44 (1H,d, J=1.9 Hz), 6.76-6.77 (1H, m), 7.00-7.04 (1H, m), 7.15-7.18 (2H, m),7.24-7.28 (1H, m), 7.34-7.47 (4H, m), 7.73 (1H, d, J=1.9 Hz).

Example 423-({4-[(Methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzonitrilehydrochloride

Using tert-butyl methyl[(5-phenyl-1H-pyrrol-3-yl)methyl]carbamate (250mg), sodium hydride (60% in oil, 175 mg) and 3-cyanobenzenesulfonylchloride (528 mg), a procedure as in Example 36 was performed to givethe title compound as pale-purple crystals (yield 195 mg, 58%).

¹H-NMR (DMSO-d₆) δ: 2.52 (3H, s), 3.98 (2H, s), 6.50 (1H, s), 7.11-7.13(2H, m), 7.35-7.49 (3H, m), 7.68-7.78 (4H, m), 8.17-8.21 (1H, m), 9.16(2H, br).

Example 43N-Methyl-1-[5-phenyl-1-(3-thienylsulfonyl)-1H-pyrrol-3-yl]methanaminehydrochloride

Using tert-butyl methyl[(5-phenyl-1H-pyrrol-3-yl)methyl]carbamate (250mg), sodium hydride (60% in oil, 140 mg) and thiophene-3-sulfonylchloride (340 mg), a procedure as in Example 36 was performed to givethe title compound as pale-purple crystals (yield 114 mg, 35%).

¹H-NMR (DMSO-d₆) δ: 2.52 (3H, s), 3.98 (2H, s), 6.45 (1H, d, J=1.8 Hz),6.99 (1H, dd, J=5.2 Hz, 1.4 Hz), 7.16-7.19 (2H, m), 7.34-7.45 (3H, m),7.69 (1H, d, J=1.8 Hz), 7.74 (1H, dd, J=5.2 Hz, 3.0 Hz), 7.98 (1H, dd,J=3.0 Hz, 1.4 Hz).

The structures of the compounds described in Reference Examples areshown in Table 1-Table 17.

TABLE 1

No. R^(1p) R^(2p) 1 phenyl CN 13 phenyl acetyl 23 2-methylphenyl CN 244-methoxyphenyl CN 25 2-trifluoromethylphenyl CNcontinued on Table 2

TABLE 2

No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) 2 H phenyl H CO₂Et Cl 3 H phenylH CO₂Et H 4 tosyl phenyl H CO₂Et H 5 tosyl phenyl H CH₂OH H 6 tosylphenyl H CHO H 7 4-fluorobenzene- phenyl H CH₂OH H sulfonyl 84-fluorobenzene- phenyl H CHO H sulfonyl 9 mesyl phenyl H CH₂OH H 10mesyl phenyl H CHO H 11 4-methoxybenzene- phenyl H CO₂Et H sulfonyl 124-methoxybenzene- phenyl H CHO H sulfonyl 14 H phenyl H CO₂Et Me 154-fluorobenzene- phenyl H CO₂Et Me sulfonyl 16 4-fluorobenzene- phenyl HCHO Me sulfonyl 17 tosyl 4-fluorophenyl H CHO H 18 tosyl 3-methylphenylH CHO H 19 tosyl 3-fluorophenyl H CHO H 20 2-methylbenzene- phenyl H CHOH sulfonyl 21 4-trifluoromethyl- phenyl H CHO H benzenesulfonyl 224-fluoro-2-methyl- phenyl H CHO H benzenesulfonyl 26 H 4-methoxyphenyl HCO₂Et H 27 H 2-trifluoro- H CO₂Et H methylphenyl 28 benzenesulfonyl4-fluorophenyl H CO₂Et H 29 4-fluorobenzene- 4-fluorophenyl H CO₂Et Hsulfonyl 30 4-trifluoromethyl- 4-fluorophenyl H CO₂Et H benzenesulfonyl31 benzenesulfonyl 4-fluorophenyl H CHO H 32 tosyl 2-methylphenyl H CHOH 33 4-fluorobenzene- 4- H CHO H sulfonyl methoxyphenyl 344-fluorobenzene- 4-fluorophenyl H CHO H sulfonyl 35 4-trifluoromethyl-4-fluorophenyl H CHO H benzenesulfonyl 36 4-fluorobenzene- 2-trifluoro-H CHO H sulfonyl methylphenyl 37 tosyl 2-trifluoro- H CHO H methylphenyl38 benzenesulfonyl phenyl H CHO Me 39 H H H CO₂Me H

continued on Table 3

TABLE 3 40 H Br H Co₂Me H 41 4-methoxybenzenesulfonyl Br H Co₂Me H 424-methoxybenzenesulfonyl Br H CHO H 43 4-methoxybenzenesulfonyl Br HCH₂NCH₃Boc H 44 tosyl phenyl H CH₂N₃ H 45 H H methyl CO₂Et H 46 H Brmethyl CO₂Et H 47 tosyl Br methyl CO₂Et H 48 tosyl phenyl methyl CO₂Et H49 tosyl phenyl methyl CHO H 50 tosyl Br H CH₂NCH₃Boc H 51benzenesulfonyl Br H Co₂Me H 52 benzenesulfonyl Br H CH₂OH H 53benzenesulfonyl Br H CHO H 54 benzenesulfonyl Br H CH₂NCH₃ H 55benzenesulfonyl Br H CH₂NCH₃Boc H 56 benzenesulfonyl 3- H CH₂NCH₃Boc Hthienyl 57 benzenesulfonyl phenyl H CH₂NCH₃Boc H 584-fluorobenzenesulfonyl Br H CH₂NCH₃Boc H 59 4-fluorobenzenesulfonyl 3-H CH₂NCH₃Boc H thienyl 60 3-chlorobenzenesulfonyl Br H CH₂NCH₃Boc H 613-chlorobenzenesulfonyl Ph H CH₂NCH₃Boc H 62 3-chlorobenzenesulfonyl 3-H CH₂NCH₃Boc H thienyl 63 3-chlorobenzenesulfonyl 4- H CH₂NCH₃Boc Hfluoro- phenyl 64 H phenyl H CH₂OH H 65 H phenyl H CHO H 66 H phenyl HCH₂NCH₃Boc Hcontinued on Table 4

TABLE 4

Ref. Ex. No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) 73 H

H CO₂Et Cl 74 H

Me CO₂Me Cl 75 H

Me CO₂Et Me 76 H

H CO₂Et Me 77 H

H CO₂Et Me 78 H

H CO₂Et Cl 79 H

H CO₂Et H 80 H

Me CO₂Me H 81 H

H CO₂Et H 82 H

H CO₂Me H 83 H

Cl CO₂Et Me 84 H

H CO₂Et F 85 H

F CO₂Et Cl 86 H

F CO₂Et H 88 H H Me CO₂Me H 89 H H Et CO₂Me H 90 H H n-Pr CO₂Me H 91 H Hi-Pr CO₂Me H 92 H H

CO₂Me H 94 H n-Bu H CO₂Et Hcontinued on Table 5

TABLE 5

Ref. Ex. No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) 95 H

H CO₂Et H 96 H H H CO₂Et Me 97 H Br Me CO₂Me H 98 H Br Et CO₂Me H 99 HBr n-Pr CO₂Me H 100 H Br i-Pr CO₂Me H 101 H Br

CO₂Me H 102 H Br H CO₂Et Me 103

Br n-Pr CO₂Me H 104

Br

CO₂Me H 105 H

n-Pr CO₂Me H 106 H

CO₂Me H 107 H

Me CH₂OH H 108 H

H CH₂OH H 109 H

Me CHO H 110 H

H CHO H 111 H

H CHO H 112 H

H CHO H 113 H

H CHO Hcontinued on Table 6

TABLE 6

Ref. Ex. No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) 139

H H CO₂Et Me 140

Br Me CO₂Me H 141

Br Me CO₂Me H 142

Br Me CO₂Et H 143

Br Me CO₂Me H 144

Br Et CO₂Me H 145

Br i-Pr CO₂Me H 146

Br H CO₂Me H 147

Br H CO₂Me H 148

Br H CO₂Et Me 149

H CO₂Et Me 150

H CO₂Et Me 151

H CO₂Et H 152

H CO₂Et H 153

H CO₂Et H 154

H CO₂Et H 155

H CO₂Et Hcontinued on Table 7

TABLE 7

Ref. Ex. No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) 156

H CO₂Et H 157

H CO₂Et H 158

Me CO₂Et Me 159

H CO₂Et Me 160

H CO₂Et Me 161

n-Pr CO₂Me H 162

CO₂Me H 163

Cl CO₂Et Me 164

H CO₂Et Cl 165

H CO₂Et F 166

F CO₂Et Cl 167

F CO₂Et H 168

n-Bu H CO₂Et H 169

H CO₂Et H 170

Me CO₂Me H 171

Me CO₂Me H 172

Me CO₂Et Hcontinued on Table 8

TABLE 8

Ref. Ex. No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) 173

Me CO₂Me H 174

H CO₂Et Me 175

H CO₂Me H 176

H H CH₂OH Me 177

Br H CH₂OH H 178

Br Et CH₂OH H 179

H CH₂OH Me 180

H CH₂OH H 181

H CH₂OH H 182

H CH₂OH Me 183

H CH₂OH Me 184

Me CH₂OH Me 185

n-Pr CH₂OH H 186

CH₂OH H 187

H CH₂OH Cl 188

H CH₂OH F 189

F CH₂OH Cl 190

F CH₂OH Hcontinued on Table 9

TABLE 9

Ref. Ex. No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) 191

H H CHO Me 192

Br Et CHO H 193

Br H CHO H 194

H CHO Cl 195

H CHO Me 196

H CHO H 197

H CHO H 198

H CHO Me 199

H CHO Me 200

Me CHO Me 201

n-Pr CHO Me 202

CHO H 203

H CHO Cl 204

H CHO F 205

F CHO Cl 206

F CHO H 207

Br Me CHO Hcontinued on Table 10

TABLE 10

Ref. Ex. No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) 208 H

Me CHO H 209 H Br H CHO H 210

H CHO Me 211

H CHO H 212

Me CHO H 213

Me CHO H 214

H CHO Me 215

Cl CHO Me 216

n-Bu H CHO H 217

H CHO H 218

H CHO H 219

H CHO H 220

H CHO H 221

H CHO H 222

H CHO Hcontinued on Table 11

TABLE 11

Ref. Ex. No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) 223

H CHO H 224

H CHO H 225

H CHO H 226

H CHO H 227

H CHO H 228

H CHO H 229

H CHO H 230

H CHO H 231

H CHO H 232

H CHO H 233

H CHO H 234

H CHO H 235

H CHO H 236

H CHO Hcontinued on Table 12

TABLE 12

Ref. Ex. No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) 237

H CHO H 238

H CHO H 239

H CHO H 240

H CHO H 241

H CHO H 242

H CHO H 243

H CHO H 244

H CHO H 245

H CHO H 246

H CHO H 247

H CHO H 248

H CHO H 249

H CHO H 250

H CHO Hcontinued on Table 13

TABLE 13

Ref. Ex. No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) 251

Me CHO H 252

Me CHO H 253

Me CHO H 254

Me CHO H 255

Me CHO H 256

Me CHO H 257

Me CHO H 258

Me CHO H 259

Me CHO H 260

Me CHO H 261

Me CHO H 262

Br H CHO Hcontinued on Table 14

TABLE 14

Ref. Ex. No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) 263 H H H CHO Me 264

H H CHO Me 265

Br H CHO Me 266

Br H CHO Me 267

H CHO Me 268

H CHO Me 269

Me CHO H 270

Br H CH₂NHMe H 271

Br i-Pr CH₂NHMe H 272

Br H

H 273

Br H

H 274

Br H

H 275

Br Et

H 276

Br i-Pr

H 277

Et

Hcontinued on Table 15

TABLE 15

Ref. Ex. No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) 278

i-Pr

H 279

H

H 280

H

H 281

H

H 282

H

H 283

H

H 284

H

H 285

H

H 286

H

H 287

H

H 288

H

H 289

H

H 290

H

Hcontinued on Table 16

TABLE 16

Ref. Ex. No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) 291

H

H 292 H Br H

H 293

Br H

H 294

H

H 295

H

H 296

H

H 297

H

H 298

H

H 299

H

H 300

H

H 301

H

H 302

H

H 303

H

H 304

H

H 305

H

Hcontinued on Table 17

TABLE 17

Ref. Ex. No. R^(1a) R^(2a) R^(3a) R^(4a) R^(5a) 306

H

H 307

H

H 308 H

H

H 309 H

H

H 310 H

H

H 311

H

H 312

H

H 313

H

H 314

H

H 315

Br H

Me 316

H

H 317

H

H

The structures of the compounds described in Examples are shown in Table18-Table 19.

TABLE 18

No. R^(1b) R^(2b) R^(3b) R^(4b) R^(5b)  1 tosyl phenyl H CH₂NHCH₃ H(hydrochloride)  2 4-phenylbenzene- phenyl H CH₂NHCH₃ H sulfonyl  3mesyl phenyl H CH₂NHCH₃ H  4 4- phenyl H CH₂NHCH₃ H methoxybenzene-(hydrochloride) sulfonyl  5 4-fluorobenzene- phenyl H CH₂NHCH₃ Mesulfonyl (hydrochloride)  6 tosyl 4-fluoro- H CH₂NHCH₃ H phenyl  7 tosyl3-methyl- H CH₂NHCH₃ H phenyl (hydrochloride)  8 tosyl 3-fluoro- HCH₂NHCH₃ H phenyl (hydrochloride)  9 2-methylbenzene- phenyl H CH₂NHCH₃H sulfonyl (hydrochloride) 10 4- phenyl H CH₂NHCH₃ H trifluoromethyl-(hydrochloride) benzenesulfonyl 11 4-fluoro-2- phenyl H CH₂NHCH₃ Hmethylbenzene- (hydrochloride) sulfonyl 12 4- phenyl H CH₂N(CH₃)₂ Htrifluoromethyl- (hydrochloride) benzenesulfonyl 13 benzenesulfonyl4-fluoro- H CH₂NHCH₃ H phenyl (hydrochloride) 14 tosyl 2- H CH₂NHCH₃ Hmethylphenyl (hydrochloride) 15 4-fluorobenzene- 4-fluoro- H CH₂NHCH₃ Hsulfonyl phenyl 16 4- 4-fluoro- H CH₂NHCH₃ H trifluoromethyl- phenylbenzenesulfonyl 17 4-fluorobenzene- 4-methoxy- H CH₂NHCH₃ H sulfonylphenyl 18 4-fluorobenzene- 2-trifluoro- H CH₂NHCH₃ H sulfonylmethylphenyl (hydrochloride) 19 tosyl 2-trifluoro- H CH₂NHCH₃ Hmethylphenyl (hydrochloride) 20 benzenesulfonyl phenyl H CH₂NHCH₃ Me(hydrochloride) 21 4- 2,4- H CH₂NHCH₃ H methoxybenzene- difluoro-(hydrochloride) sulfonyl phenylcontinued on Table 19

TABLE 19 22 4- 4-phenoxy H CH₂NHCH₃ H methoxybenzene- phenyl(hydrochloride) sulfonyl 23 4- 2-naphthyl H CH₂NHCH₃ H methoxybenzene-(hydrochloride) sulfonyl 24 4- 3-aminophenyl H CH₂NHCH₃ Hmethoxybenzene- (dihydrochloride) sulfonyl 25 4- 5-pyridyl H CH₂NHCH₃ Hmethoxybenzene- (dihydrochloride) sulfonyl 26 tosyl phenyl H CH₂NH₂ H(hydrochloride) 27 tosyl phenyl methyl CH₂NHCH₃ H (hydrochloride) 28tosyl 3-cyanophenyl H CH₂NHCH₃ H (hydrochloride) 29 tosyl 4-cyanophenylH CH₂NHCH₃ H (hydrochloride) 30 benzenesulfonyl 3-thienyl H CH₂NHCH₃ H(hydrochloride) 31 benzenesulfonyl phenyl H CH₂NHCH₃ H (hydrochloride)32 4-fluorobenzene- 3-thienyl H CH₂NHCH₃ H sulfonyl (hydrochloride) 333-chlorobenzene- phenyl H CH₂NHCH₃ H sulfonyl (hydrochloride ) 343-chlorobenzene- 3-thienyl H CH₂NHCH₃ H sulfonyl (hydrochloride) 353-chlorobenzene- 4-fluoro H CH₂NHCH₃ H sulfonyl phenyl (hydrochloride)36 4-chlorobenzene- phenyl H CH₂NHCH₃ H sulfonyl (hydrochloride) 373,4-difluoro- phenyl H CH₂NHCH₃ H benzenesulfonyl (hydrochloride) 382,3-dihydro-1- phenyl H CH₂NHCH₃ H benzofuran-5- (0.5 oxalate)ylsulfonyl 39 butylsulfonyl phenyl H CH₂NHCH₃ H (0.5 oxalate) 404-isopropoxy- phenyl H CH₂NHCH₃ H benzenesulfonyl (0.5 oxalate) 41 3-phenyl H CH₂NHCH₃ H methoxybenzene- (hydrochloride) sulfonyl 423-cyanobenzene- phenyl H CH₂NHCH₃ H sulfonyl (hydrochloride) 43 3-phenyl H CH₂NHCH₃ H thienylsulfonyl (hydrochloride)

The compounds of Examples 44-116 were synthesized by the followingmethods.

LC-MS measurement condition: in the following Examples, HPLC-massspectrum (LC-MS) was measured under the following conditions.

Measurement device: ZMD Micromass, and HP1100 Agilent Technologies

Column: CAPCELL PAK C18UG120, S-3 μm, 1.5×35 mm

Solvent: SOLUTION A; 0.05% trifluoroacetic acid containing water,SOLUTION B; 0.04% trifluoroacetic acid containing acetonitrile

Gradient cycle: 0.00 min (SOLUTION A/SOLUTION B=90/10), 2.00 min(SOLUTION A/SOLUTION B=5/95), 2.75 min (SOLUTION A/SOLUTION B=5/95),2.76 min (SOLUTION A/SOLUTION B=90/10), 3.45 min (SOLUTION A/SOLUTIONB=90/10)

Injection volume: 2 μl

Flow rate: 0.5 mL/min, detection: UV 220 nm

Ionization method: electron impact ionization method (Electron SprayIonization: ESI)

Preparative HPLC conditions: in the following Reference Examples andExamples, purification by preparative HPLC was conducted under thefollowing conditions.

Equipment: high throughput purified system Gilson

Column: YMC CombiPrep ODS-A, S-5 μm, 50×20 mm

Solvent: SOLUTION A; 0.1% trifluoroacetic acid containing water,SOLUTION B; 0.1% trifluoroacetic acid containing acetonitrile

Gradient cycle: 0.00 min (SOLUTION A/SOLUTION B=90/10), 1.00 min(SOLUTION A/SOLUTION B=90/10), 4.00 min (SOLUTION A/SOLUTION B=10/95),8.50 min (SOLUTION A/SOLUTION B=10/95), 8.60 min (SOLUTION A/SOLUTIONB=90/10), 8.70 min (SOLUTION A/SOLUTION B=90/10)

Flow rate: 20 mL/min, detection: UV 220 nm

Other Conditions:

¹H-NMR spectrum was measured by Mercury 300 (300 MHz) usingtetramethylsilane as the internal standard, and all δ values are shownin ppm. Unless otherwise specified, the numerical values shown for mixedsolvents are volume mixing ratios of respective solvents. Unlessotherwise specified, % means weight %. The room temperature (ambienttemperature) in the present specification shows a temperature from about10° C. to about 35° C. In addition, as a microwave reactor, EmrysOptimizer of Personal Chemistry was used.

Example 441-[5-(3-Furyl)-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrrol-3-yl]-N-methylmethanaminetrifluoroacetate

tert-Butyl({5-bromo-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate(0.053 mmol), furan-3-boronic acid (0.100 mmol),tetrakis(triphenylphosphine)palladium (0.0025 mmol) were dissolved in amixed solvent of dimethoxyethane (1.0 mL), ethanol (0.3 mL) andacetonitrile (0.2 mL), 0.5 mol/l aqueous sodium carbonate solution (0.3mL) was added, and the mixture was subjected to microwave irradiation ina sealed reaction container and stirred at 150° C. for 4 min. Aftercompletion of the reaction, water (2 mL) and ethyl acetate (2 mL) wereadded to the reaction mixture and the mixture was stirred for a while.The organic layer was passed through a PTFE tube(polytetrafluoroethylene membrane processed tube) to give a solutioncontaining the object compound. The solvent was evaporated under reducedpressure, a 10% solution (0.5 mL) of tetrafluoroacetic acid indichloromethane was added to the residue and the mixture was stood at50° C. for 3 hr. After concentration, the residue was purified bypreparative HPLC to give the title compound (13.5 mg, LC-MS purity 97%).

Examples 45-86

The compounds of Example 45 to Example 86 were obtained by reaction withvarious boronic acids in the same manner as in Example 44 (Tables 20 and21). The proton NMR data of the representative compounds are shown inthe following Table 22.

TABLE 20

LC/MS HPLC purity m/e Ex. N Ar R^(q) (%) (M⁺ + 1) 45 2 3-pyridyl methoxy 97 358 46 1 3-thienyl methoxy  96 363 47 1 p-tolyl methoxy  96 371 48 14-cyanophenyl methoxy 100 382 49 1 3,5- methoxy  96 385 dimethylphenyl50 1 4-methoxyphenyl methoxy  97 387 51 1 4-chlorophenyl methoxy  91 39152 1 4-acetylphenyl methoxy  98 399 53 1 3-acetylphenyl methoxy  97 39954 1 4-aminocarbonyl- methoxy  98 400 phenyl 55 2 4-(N,N- methoxy  98400 dimethylamino)- phenyl 56 1 4-(methylthio)- methoxy  81 403 phenyl57 1 benzo[b]- methoxy  99 413 thiophen-2-yl 58 1 3-(acetylamino)-methoxy  93 414 phenyl 59 1 2,4- methoxy  97 417 dimethoxyphenyl 60 13-(trifluoro- methoxy  94 425 methyl)phenyl 61 1 4-(trifluoro- methoxy 87 441 methoxy)phenyl 62 1 2- methoxy  99 415 isopropoxyphenyl 63 13-(6- methoxy  93 388 methoxy)pyridyl 64 1 3-cyanophenyl methoxy  98 38265 1 3-furyl methyl  98 331 66 2 3-pyridyl methyl 100 342 67 1 3-thienylmethyl  99 347 68 1 p-tolyl methyl  96 355 69 1 4-cyanophenyl methyl  98366 70 1 3,5- methyl  93 369 dimethylphenyl 71 1 4-methoxyphenyl methyl 99 371 72 1 4-chlorophenyl methyl  93 375 73 1 4-acetylphenyl methyl 98 383 74 1 3-acetylphenyl methyl  98 383 75 1 4-aminocarbonyl- methyl 98 384 phenylcontinued on Table 21

TABLE 21 76 2 4-(N,N- methyl 99 384 dimethylamino)phenyl 77 14-(methylthio)phenyl methyl 96 387 78 1 benzo[b]thiophen-2-yl methyl 99397 79 1 3-(acetylamino)phenyl methyl 89 398 80 1 2,4-dimethoxyphenylmethyl 99 401 81 1 3- methyl 81 409 (trifluoromethyl)phenyl 82 1 4-methyl 89 425 (trifluoromethoxy)phenyl 83 1 2-isopropoxyphenyl methyl 92399 84 1 3-(hydroxymethyl)phenyl methyl 91 371 85 1 3-(6-methoxy)pyridylmethyl 99 372 86 1 3-cyanophenyl methyl 98 366

TABLE 22 compound ¹H-NMR(DMSO-d₆, 300 MHz); δ Ex. 48 2.50(3H, s),3.82(3H, s), 3.99(2H, s), 6.49(1H, s), 7.03(2H, d, J = 9.0 Hz), (TFAsalt) 7.30-7.46(4H, m), 7.74(1H, s), 7.87(2H, d, J = 6.0 Hz), 8.65(2H,brs) Ex. 77 2.36(3H, s), 2.50(3H, s), 3.36(3H, s), 3.98(2H, s), 6.33(1H,s), 7.09(2H, (TFA salt) d, J = 6.0 Hz), 7.20-7.40(6H, m), 7.66(1H, s),8.69(2H, s)

Example 871-{1-[(2,5-Dichloro-3-thienyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanaminetrifluoroacetate

A solution of tert-butylmethyl[(5-phenyl-1H-pyrrol-3-yl)methyl]carbamate (0.06 mmol) in DMF (1.8mL) was added to sodium hydride (60% in oil, 0.6 mmol), and the mixturewas stirred at room temperature for 10 min.2,5-Dichlorothiophene-3-sulfonyl chloride (0.18 mmol) was added and themixture was stirred at room temperature for 30 min. Water (2 mL) wasadded and the mixture was stirred and extracted with dichloromethane (3mL). The extract was washed twice with water (2 mL) and aminomethylscavenger Lantern (trade name) resin (Mimotopes Pty Ltd., 0.25 mmol) wasadded to the obtained solution. The mixture was stirred at roomtemperature for 1 hr and Lantern was removed. trifluoroacetic acid (0.4mL) was added to the obtained solution, and the mixture was stood atroom temperature for 3 days. The solvent was evaporated, and theobtained residue was purified by preparative HPLC to give the titlecompound (8.1 mg, LC-MS purity 100%).

Examples 88-116

The compounds of Example 88 to Example 116 were obtained by reactionwith various sulfonyl chlorides in the same manner as in Example 87(Table 23). The proton NMR data of the representative compounds areshown in the following Table 24.

TABLE 23

LC/MS HPLC purity m/e Ex. R^(r) (%) (M⁺ + 1)  88 4-biphenyl 100 403  89m-toluyl 100 341  90 2,4-dichlorophenyl 100 395  912-methoxy-4-methylphenyl 100 371  92 2-chlorophenyl 100 361  934-carboxyphenyl  99 371  94 3,5-dimethylphenyl 100 355  953,5-dichlorophenyl  93 395  96 4-tert-butylphenyl  99 383  97 n-propyl 99 293  98 ethyl 100 279  99 3,4-dimethoxyphenyl  95 387 1003-chlorophenyl 100 361 101 4-cyanophenyl  98 352 102 3-cyanophenyl  98352 103 2-cyanophenyl  99 352 104 2,1,3-benzothiadiazol-4-yl  96 385 1053,4-dichlorophenyl  99 395 106 3-thienyl  96 333 107 phenyl 100 327 1081-naphthyl  97 377 109 p-styryl  99 353 110 4-ethylphenyl 100 355 1113,5-dichlorophenyl  99 395 112 isopropyl 100 293 113 2-(1-naphthyl)ethyl 99 405 114 2-naphthyl  99 377 115 2,4,6-trimethylphenyl 100 369 1164-bromophenyl  99 405

TABLE 24 compound ¹H-NMR(DMSO-d₆, 300 MHz); δ Ex. 91 2.33(3H, s),2.63(3H, s), 3.71(3H, s), 4.02(2H, s), 6.20(1H, s), 6.51(1H, (TFA salt)d, J = 8.1 Hz), 6.66(1H, s), 6.99(2H, d, J = 7.5 Hz), 7.07(1H, d, J =8.3 Hz), 7.14(2H, t, J = 7.6 Hz), 7.23(1H, d, J = 7.3 Hz), 7.61(1H, s),9.42(1H, s) Ex. 98 1.05(3H, t, J = 7.3 Hz), 2.63(3H, s), 2.93(2H, q, J =7.5 Hz), 3.98(2H, s), (TFA salt) 6.40(1H, d, J = 1.9 Hz), 7.31-7.55(6H,m), 9.68(1H, s) Ex. 106 2.60(3H, s), 3.97(2H, s), 6.26(1H, s), 6.90(1H,d, J = 5.3 Hz), 7.18(2H, (TFA salt) d, J = 7.3 Hz), 7.21-7.49(5H, m),7.56(1H, s), 9.61(1H, s) Ex. 112 1.09(6H, d, J = 6.8 Hz), 2.63(3H, s),2.88-3.04(1H, m), 3.99(2H, s), (TFA salt) 6.40(1H, d, J = 1.9 Hz),7.32-7.51(6H, m), 9.65(1H, s)

Example 1171-(2-Chloro-5-phenyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride

2-Chloro-5-phenyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}-1H-pyrrole-3-carbaldehyde(160 mg) was dissolved in methanol (20 mL), 40% methylamine methanolsolution (150 mg) was added at room temperature, and the mixture wasstirred for 30 min. Sodium borohydride (44 mg) was added at roomtemperature, and the mixture was stirred for 10 min. 1 mol/LHydrochloric acid (10 mL) was added, and the mixture was stirred for 5min. The reaction mixture was alkalized with a saturated aqueous sodiumhydrogencarbonate solution, and extracted with ethyl acetate. Theextract was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by basic silica gel column chromatography (eluent: hexane-ethylacetate=1:4→0:1), and dissolved in ethyl acetate (5 mL). A 4 mol/Lhydrogen chloride-ethyl acetate solution (1 mL) was added, and themixture was concentrated under reduced pressure. The residue wascrystallized from ethyl acetate to give the title compound as colorlesscrystals (yield 98 mg, 55%).

¹H-NMR (DMSO-d₆) δ: 2.43 (3H, s), 3.89 (2H, s), 6.65 (1H, s), 7.38-7.48(5H, m), 7.85 (2H, d, J=8.4 Hz), 8.05 (2H, d, J=8.4 Hz).

Example 1181-{1-[(3-Chlorophenyl)sulfonyl]-2-methyl-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanaminehydrochloride

Using1-[(3-chlorophenyl)sulfonyl]-2-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde(171 mg), methylammonium chloride (311 mg) and sodium cyanoborohydride(103 mg), a procedure as in Example 4 was performed to give the titlecompound as a colorless oil (yield 64 mg, 34%).

¹H-NMR (CDCl₃) δ: 2.44 (3H, brs), 2.56 (3H, s), 3.87 (2H, brs), 6.47(1H, s), 7.18-7.22 (2H, m), 7.26-7.36 (6H, m), 7.47-7.50 (1H, m), 9.78(2H, brs).

Example 119N-Methyl-1-(5-phenyl-1-{[4-(trifluoromethoxy)phenyl]sulfonyl}-1H-pyrrol-3-yl)methanaminehydrochloride

To a solution (12 mL) of5-phenyl-1-{[4-(trifluoromethoxy)phenyl]sulfonyl}-1H-pyrrole-3-carbaldehyde(0.41 g) in methanol were added methylammonium chloride (0.86 g) andsodium cyanoborohydride (0.27 g), and the mixture was stirred at roomtemperature for 24 hr. The reaction mixture was concentrated underreduced pressure, saturated aqueous sodium hydrogencarbonate solutionwas added, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The residue was purified bybasic silica gel column chromatography (eluent: hexane-ethylacetate=2:1→1:1) to give free base of the title compound as an oil (0.32g). The obtained oil (0.32 g) was dissolved in ethyl acetate (5 mL). A 4mol/L hydrogen chloride-ethyl acetate solution (4 mL) was added, and themixture was concentrated under reduced pressure. The residue wascrystallized from ethyl acetate to give the title compound as whitecrystals (yield 0.29 g, 63%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 3.99 (2H, s), 6.47 (1H, d, J=1.9 Hz),7.10-7.15 (2H, m), 7.32-7.43 (3H, m), 7.45-7.54 (4H, m), 7.75 (1H, d,J=1.7 Hz), 9.04 (2H, s).

Example 120N-Methyl-1-[5-phenyl-1-(2-thienylsulfonyl)-1H-pyrrol-3-yl]methanaminehydrochloride

5-Phenyl-1-(2-thienylsulfonyl)-1H-pyrrole-3-carbaldehyde (180 mg) wasdissolved in methanol (20 mL), a 40% methylamine methanol solution (220mg) was added at room temperature, and the mixture was stirred for 30min. Sodium borohydride (64 mg) was added at room temperature, and themixture was stirred for 10 min. 1 mol/L Hydrochloric acid (20 mL) wasadded, and the mixture was stirred for 5 min. The reaction mixture wasalkalized with a saturated aqueous sodium hydrogencarbonate solution andextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by basic silica gel columnchromatography (eluent: hexane-ethyl acetate=1:4→0:1), and dissolved inethyl acetate (5 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution(1 mL) was added, and the mixture was concentrated under reducedpressure. The residue was crystallized from ethyl acetate to give thetitle compound as colorless crystals (yield 171 mg, 82%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 3.98 (2H, s), 6.49 (1H, d, J=1.8 Hz),7.12 (1H, dd, J=3.9, 5.0 Hz), 7.22-7.25 (2H, m), 7.32 (1H, dd, J=1.4,3.9 Hz), 7.36-7.46 (3H, m), 7.69 (1H, d, J=1.8 Hz), 8.08 (1H, dd, J=1.4,5.0 Hz), 9.10 (2H, br).

Example 121N-Methyl-1-[2-methyl-1-(phenylsulfonyl)-5-(3-thienyl)-1H-pyrrol-3-yl]methanaminehydrochloride

To a solution of2-methyl-1-(phenylsulfonyl)-5-(3-thienyl)-1H-pyrrole-3-carbaldehyde (307mg) in tetrahydrofuran (5 mL) were added 40% methylamine methanolsolution (0.4 mL), and anhydrous magnesium sulfate (268 mg), and themixture was stirred at room temperature for 14 hr. To the reactionmixture was added sodium borohydride (45 mg) at room temperature, andthe mixture was stirred for 30 min, and concentrated under reducedpressure. Saturated aqueous sodium hydrogencarbonate solution was addedto the residue, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated aqueous sodium hydrogencarbonatesolution, water and saturated brine, and dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by basic silica gel column chromatography (eluent:ethyl acetate) to give free base of the title compound as a yellow oil.To solution (5 mL) of the obtained free base in methanol was added 4mol/L hydrogen chloride-ethyl acetate solution (2.0 mL), and the mixturewas stirred for 2 hr. The reaction mixture was concentrated underreduced pressure, and the residue was recrystallized from ethanol togive the title compound as white crystals (yield 85 mg, 23%).

¹H-NMR (CDCl₃) δ: 2.43 (3H, brt, J=5.1 Hz), 2.55 (3H, s), 3.86 (2H,brs), 6.48 (1H, s), 7.00-7.02 (1H, m), 7.05-7.06 (1H, m), 7.18-7.20 (1H,m), 7.35-7.44 (4H, m), 7.50-7.55 (1H, m), 9.72 (2H, brs).

Example 1221-[5-(4-Fluorophenyl)-2-methyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

To a solution (20 mL) of5-(4-fluorophenyl)-2-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde(0.40 g) in methanol were added methylammonium chloride (0.95 g) andsodium cyanoborohydride (0.30 g), and the mixture was stirred at roomtemperature for 20 hr. The reaction mixture was concentrated underreduced pressure, saturated aqueous sodium hydrogencarbonate solutionwas added, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The residue was purified bybasic silica gel column chromatography (eluent: hexane-ethylacetate=1:0→1:2) to give free base of the title compound as an oil (0.30g). The obtained oil (0.30 g) was dissolved in ethyl acetate (6 mL), anda 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL) was added. Themixture was concentrated under reduced pressure, and the residue wascrystallized from ethyl acetate to give the title compound as colorlesscrystals (yield 0.31 g, 92%).

¹H-NMR (DMSO-d₆) δ: 2.44 (3H, s), 2.50 (3H, s), 3.91 (2H, s), 6.43 (1H,s), 7.16-7.30 (4H, m), 7.44-7.49 (2H, m), 7.57 (2H, t, J=7.8 Hz),7.69-7.75 (1H, m), 8.97 (2H, brs).

Example 123N-Ethyl-1-[5-(4-fluorophenyl)-2-methyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methylaminehydrochloride

To a solution (15 mL) of5-(4-fluorophenyl)-2-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde(0.30 g) in methanol were added ethylamine (content about 70%, 0.17 g)and sodium cyanoborohydride (0.16 g, 2.6 mmol), and the mixture wasstirred at room temperature for 24 hr. The reaction mixture wasconcentrated under reduced pressure, water was added, and the mixturewas extracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was purified by basic silica gel columnchromatography (eluent: hexane-ethyl acetate=1:0→1:2) to give free baseof the title compound as an oil (0.095 g). The obtained oil (0.095 g)was dissolved in ethyl acetate (3 mL). A 4 mol/L hydrogen chloride-ethylacetate solution (1 mL) was added, and the mixture was concentratedunder reduced pressure. The residue was crystallized from ethyl acetateto give the title compound as colorless crystals (yield 0.082 g, 23%).

¹H-NMR (DMSO-d₆) δ: 1.17 (3H, t, J=7.2 Hz), 2.48 (3H, s), 3.90 (2H, s),6.47 (1H, s), 7.16-7.31 (4H, m), 7.44-7.50 (2H, m), 7.58 (2H, t, J=7.8Hz), 7.72 (1H, t, J=7.4 Hz), 8.94 (2H, brs).

Example 1241-[2,4-Dimethyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

Using 2,4-dimethyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde(585 mg), a procedure as in Example 121 was performed to give the titlecompound as white crystals (yield 140 mg, 22%).

¹H-NMR (CDCl₃) δ: 1.90 (3H, s), 2.41 (3H, brs), 2.64 (3H, s), 3.92 (2H,brs), 7.07-7.10 (2H, m), 7.26-7.45 (7H, m), 7.51-7.56 (1H, m), 9.62 (2H,brs).

Example 125N-Methyl-1-[5-phenyl-1-(phenylsulfonyl)-4-propyl-1H-pyrrol-3-yl]methanaminehydrochloride

Using 5-phenyl-1-(phenylsulfonyl)-4-propyl-1H-pyrrole-3-carbaldehyde(1.33 g), 40% methylamine methanol solution (877 mg) and sodiumborohydride (474 mg), a procedure as in Example 9 was performed.Recrystallization from a mixed solvent of ethyl acetate and ethanol gavethe title compound as colorless crystals (yield 515 mg, 34%).

¹H-NMR (CDCl₃) δ: 0.70 (3H, t, J=7.5 Hz), 1.20-1.29 (2H, m), 2.16-2.21(2H, m), 2.71 (3H, s), 4.08 (2H, s), 6.95-6.99 (2H, m), 7.25-7.54 (8H,m), 7.96 (1H, s), 9.83 (2H, br).

Example 1261-[4,5-Diphenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine

4,5-Diphenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (202 mg) wasdissolved in methanol (2 mL) and tetrahydrofuran (2 mL), 40% methylaminemethanol solution (0.5 mL) was added at room temperature, and themixture was stirred for 15 min. To the reaction mixture was added sodiumborohydride (22 mg) at room temperature, and the mixture stirred for 1hr. The reaction mixture was concentrated under reduced pressure, to theresidue was added saturated aqueous sodium hydrogencarbonate solution,and the mixture was extracted with ethyl acetate. The extract was washedwith saturated aqueous sodium hydrogencarbonate solution, water andsaturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby basic silica gel column chromatography (eluent: ethyl acetate) togive the title compound as white crystals (yield 181 mg, 87%).

¹H-NMR (CDCl₃) δ: 1.39 (1H, brs), 2.40 (3H, s), 3.61 (2H, s), 6.95-7.02(4H, m), 7.08-7.19 (5H, m), 7.21-7.37 (5H, m), 7.46-7.52 (2H, m).

Example 1271-[2-Chloro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

2-Chloro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (440 mg)was dissolved in methanol (20 mL), 40% methylamine methanol solution(494 mg) was added at room temperature, and the mixture was stirred for30 min. Sodium borohydride (144 mg) was added at room temperature, andthe mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (20 mL)was added, and the mixture was stirred for 5 min. The reaction mixturewas alkalized with a saturated aqueous sodium hydrogencarbonate solutionand extracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by basic silica gel columnchromatography (eluent: hexane-ethyl acetate=3:7→0:1), and dissolved inethyl acetate (5 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution(1 mL) was added, and the mixture was concentrated under reducedpressure. The residue was crystallized from ethyl acetate to give thetitle compound as colorless crystals (yield 308 mg, 61%).

¹H-NMR (DMSO-d₆) δ: 2.43 (3H, s), 3.89 (2H, s), 6.61 (1H, s), 7.36-7.46(5H, m), 7.62-7.69 (4H, m), 7.75-7.82 (1H, m), 8.97 (2H, br).

Example 1281-[2-Fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

2-Fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (110 mg)was dissolved in methanol (20 mL), 40% methylamine methanol solution(130 mg) was added at room temperature, and the mixture was stirred for30 min. Sodium borohydride (38 mg) was added at room temperature, andthe mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (20 mL)was added, and the mixture was stirred for 5 min. The reaction mixturewas alkalized with a saturated aqueous sodium hydrogencarbonate solutionand extracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by basic silica gel columnchromatography (eluent: hexane-ethyl acetate=3:7→0:1), and dissolved inethyl acetate (5 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution(1 mL) was added, and the mixture was concentrated under reducedpressure. The residue was crystallized from ethyl acetate to give thetitle compound as pale-yellow crystals (yield 32 mg, 25%).

¹H-NMR (DMSO-d₆) δ: 2.43 (3H, br), 3.88 (2H, br), 6.38 (1H, d, J=5.5Hz), 7.28-7.31 (2H, m), 7.40-7.44 (3H, m), 7.58-7.67 (4H, m), 7.78-7.84(1H, m), 9.00 (2H, br).

Example 1291-[2-Chloro-4-fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

2-Chloro-4-fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde(140 mg) was dissolved in methanol (10 mL), 40% methylamine methanolsolution (150 mg) was added at room temperature, and the mixture wasstirred for 30 min. Sodium borohydride (44 mg) was added at roomtemperature, and the mixture was stirred for 10 min. 1 mol/LHydrochloric acid (20 mL) was added, and the mixture was stirred for 5min. The reaction mixture was alkalized with a saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was purified bybasic silica gel column chromatography (eluent: hexane-ethylacetate=3:7→0:10), and dissolved in ethyl acetate (5 mL). A 4 mol/Lhydrogen chloride-ethyl acetate solution (1 mL) was added, and themixture was concentrated under reduced pressure. The residue wascrystallized from ethyl acetate-diisopropyl ether to give the titlecompound as colorless crystals (yield 19 mg, 12%).

¹H-NMR (DMSO-d₆) δ: 2.44 (3H, s), 3.97 (2H, s), 7.33-7.42 (2H, m),7.48-7.51 (3H, m), 7.67-7.70 (4H, m), 7.80-7.86 (1H, m), 8.94 (2H, br).

Example 1301-[4-Fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

4-Fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (10 mg)was dissolved in methanol (5 mL), 40% methylamine methanol solution (236mg) was added at room temperature, and the mixture was stirred for 30min. Sodium borohydride (12 mg) was added at room temperature, and the 5mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (20 mL) wasadded, and the mixture was stirred for 5 min. The reaction mixture wasalkalized with a saturated aqueous sodium hydrogencarbonate solution andextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was dissolved in ethyl acetate (5 mL). A 4mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, and themixture was concentrated under reduced pressure. The residue wascrystallized from ethyl acetate to give the title compound as colorlesscrystals (yield 1 mg, 9%).

MS (ESI+): 345 (M+H)

Example 131N-Methyl-1-{2-methyl-1-[(3-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methanaminehydrochloride

To a solution (5 mL) of2-methyl-1-[(3-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde(245 mg) in methanol was added 40% methylamine-methanol solution (0.17mL), and the mixture was stirred at room temperature for 30 min. To thereaction mixture was added sodium tetrahydroborate (82 mg), and themixture was stirred at room temperature for 3 hr. The reaction mixturewas concentrated under reduced pressure, water was added to the residue,and the mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby basic silica gel column chromatography (eluent: hexane-ethylacetate=9:1→ethyl acetate). The obtained colorless oil was dissolved inethyl acetate (5 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution(0.5 mL) was added, and the mixture was left standing in a freezer at−20° C. for 18 hr. The precipitated crystals were collected byfiltration, and vacuum-dried to give the title compound as a colorlesssolid (yield 42 mg, 15%).

¹H-NMR (DMSO-d₆) δ: 2.31 (3H, s), 2.43 (3H, s), 2.48 (3H, s), 3.90 (2H,s), 6.41 (1H, s), 7.15-7.60 (9H, m), 8.92 (2H, br).

Example 132N-Methyl-1-[1-(2-methylpyrimidin-5-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]methanaminedihydrochloride

1-[(2-Methyl-5-pyrimidine)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde(148 mg) was dissolved in absolute tetrahydrofuran (10 mL), 2 mol/Lmethylamine-tetrahydrofuran solution (1.25 mL) was added, and themixture was stirred overnight at room temperature. The reaction mixturewas added to a solution of sodium borohydride (95 mg) in methanol (3.0mL), and the mixture was stirred at the same temperature for 20 min. Thereaction mixture was diluted with ethyl acetate, washed with saturatedbrine, and dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was dissolved intetrahydrofuran (20 mL), di-tert-butyl bicarbonate (0.55 g), sodiumhydrogencarbonate (0.25 g) and water (10 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed successively with saturated aqueoussodium hydrogencarbonate solution and saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was dissolved in tetrahydrofuran (20 mL),manganese dioxide (75% chemical-treated product, 1.5 g) was added, andthe mixture was stirred at room temperature for 1 hr. The reactionproduct was filtered through celite, and the celite was washed withethyl acetate. The filtrate was concentrated under reduced pressure, andthe residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→1:1) to give N-Boc compound of the titlecompound. The obtained N-Boc compound was dissolved in ethanol (1 mL)and added a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL). Themixture was stirred at room temperature for 3 hr, and the solvent wasevaporated under reduced pressure to give a solid (67 mg). The solid wasrecrystallized from ethanol to give the title compound as a colorlesssolid (yield 34 mg, 18%).

¹H-NMR (DMSO-d₆) δ: 2.53 (3H, s), 2.70 (3H, s), 3.98 (2H, s), 6.50 (1H,s), 7.18-7.20 (2H, m), 7.38-7.47 (3H, m), 7.76-7.77 (1H, m), 8.59 (2H,s), 8.88 (2H, br), 1H not detected.

Example 133N-Methyl-1-{4-methyl-[1-(3-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methanaminehydrochloride

To a solution (15 mL) of4-methyl-1-[(3-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde(0.50 g) in methanol were added methylammonium chloride (1.0 g) andsodium cyanoborohydride (0.28 g), and the mixture was stirred at roomtemperature for 2 hr. To the reaction mixture was added saturatedaqueous sodium hydrogencarbonate solution, and the mixture was extractedwith ethyl acetate. The extract was washed with saturated aqueous sodiumhydrogencarbonate solution, water and saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→0:1) to give free base of the title compound.To a solution (10 mL) of the obtained free base in ethyl acetate wasadded a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL). Thesolution was concentrated under reduced pressure, and the residue wasrecrystallized from ethanol-ethyl acetate to give the title compound asa colorless solid (yield 208 mg, 36%).

¹H-NMR (DMSO-d₆) δ: 1.77 (3H, s), 2.26 (3H, s), 2.55 (3H, s), 3.96 (2H,s), 6.96-6.99 (2H, m), 7.08 (1H, s), 7.20-7.21 (1H, m), 7.35-7.52 (5H,m), 7.73 (1H, s), 9.07 (2H, br).

Example 1341-{[1-(4-Fluorophenyl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanaminehydrochloride

To a solution (3 mL) of1-[(4-fluorophenyl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde(0.23 g) in tetrahydrofuran was added 2 mol/Lmethylamine-tetrahydrofuran solution (0.9 mL), and the mixture wasstirred at room temperature for 12 hr. The reaction mixture was added toa solution (5 mL) of sodium borohydride (68 mg) in methanol, and themixture was stirred at room temperature for 30 min. Water was added tothe reaction mixture, and the mixture was extracted with ethyl acetate.The extract was washed with saturated aqueous sodium hydrogencarbonatesolution, water and saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by basic silica gel column chromatography (eluent: hexane-ethylacetate=9:1→0:1) to give free base of the title compound. To a solution(3 mL) of the obtained free base in ethyl acetate was added a 4 mol/Lhydrogen chloride-ethyl acetate solution (0.5 mL). The mixture was leftstanding at room temperature for 30 min, and the precipitated crystalswere collected by filtration to give the title compound as a colorlesssolid (yield 172 mg, 48%).

¹H-NMR (DMSO-d₆) δ: 1.78 (3H, s), 2.57 (3H, s), 3.98 (2H, s), 6.98-7.01(2H, m), 7.35-7.45 (7H, m), 7.74 (1H, s), 9.01 (2H, br).

Example 135N-Methyl-1-[2-methyl-1-(pyridin-3-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]methanaminedihydrochloride

Using2-methyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(235 mg), a procedure as in Example 9 was performed to give 1 equivalentof ethanolate of the title compound as a solid (yield 110 mg, 39%).

¹H-NMR (DMSO-d₆) δ: 1.06 (3H, t, J=7.2 Hz), 2.43-2.50 (6H, m), 3.44 (2H,dd, J=7.2, 14.1 Hz), 3.91-3.94 (2H, m), 6.47 (1H, s), 7.21-7.43 (2H, m),7.36-7.41 (3H, m), 7.56-7.63 (1H, m), 7.82-7.88 (1H, m), 8.53 (1H, s),8.87-8.93 (3H, m), 2H not detected.

Example 1361-[4-Chloro-2-methyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

Using4-chloro-2-methyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde(301 mg), 40% methylamine methanol solution (195 mg) and sodiumborohydride (106 mg), a procedure as in Example 9 was performed.Recrystallization from a mixed solvent of ethyl acetate and ethanol gavethe title compound as colorless crystals (yield 146 mg, 42%).

¹H-NMR (CDCl₃) δ: 2.55 (3H, s), 2.77 (3H, s), 4.05 (2H, s), 7.13-7.16(2H, m), 7.32-7.45 (7H, m), 7.47-7.59 (1H, m), 9.73 (1H, br), 1H notdetected.

Example 1371-[5-Butyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

Using 5-butyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (553 mg), aprocedure as in Example 134 was performed to give the title compound asa colorless solid (yield 425 mg, 65%).

¹H-NMR (DMSO-d₆) δ: 0.79-0.85 (3H, m), 1.24-1.48 (4H, m), 2.48 (3H, s),2.58-2.63 (2H, m), 3.91 (2H, s), 6.25 (1H, s), 7.54 (1H, s), 7.66-7.88(5H, m), 8.91 (2H, br).

Example 1381-[5-Cyclohexyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

Using 5-cyclohexyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (424mg), a procedure as in Example 134 was performed to give the titlecompound as a colorless solid (yield 321 mg, 49%).

¹H-NMR (DMSO-d₆) δ: 1.10-1.35 (5H, m), 1.53-1.67 (5H, m), 2.48 (3H, s),2.80-2.84 (1H, m), 3.90 (2H, s), 6.29 (1H, s), 7.51 (1H, s), 7.65-7.70(2H, m), 7.76-7.87 (3H, m), 9.00 (2H, br).

Example 1391-[5-Cyclopropyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

Using 5-cyclopropyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (247mg), a procedure as in Example 134 was performed to give the titlecompound as a colorless solid. (yield 175 mg, 59%)

¹H-NMR (DMSO-d₆) δ: 0.22-0.27 (2H, m), 0.75-0.81 (2H, m), 1.97-2.05 (1H,m), 2.47 (3H, s), 3.87 (2H, s), 6.09 (1H, s), 7.55 (1H, s), 7.66-7.91(5H, m), 8.92 (2H, br).

Example 140N-Methyl-1-(1-{[3-(methylsulfonyl)phenyl]sulfonyl}-5-phenyl-1H-pyrrol-3-yl)methanaminehydrochloride

1-{[3-(Methylsulfonyl)phenyl]sulfonyl}-5-phenyl-1H-pyrrole-3-carbaldehyde(160 mg) was dissolved in methanol (20 mL), 40% methylamine methanolsolution (160 mg) was added at room temperature, and the mixture wasstirred for 30 min. Sodium borohydride (32 mg) was added at roomtemperature, and the mixture was stirred for 10 min. 1 mol/LHydrochloric acid (20 mL) was added, and the mixture was stirred for 5min. The reaction mixture was alkalized with a saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was dissolved inmethanol (5 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (1mL) was added, and the mixture was concentrated under reduced pressure.The residue was crystallized from tetrahydrofuran to give the titlecompound as colorless crystals (yield 150 mg, 83%).

¹H-NMR (DMSO-d₆) δ: 2.49 (3H, s), 3.26 (3H, s), 3.98 (2H, s), 6.49 (1H,d, J=1.8 Hz), 7.13-7.17 (2H, m), 7.34-7.46 (3H, m), 7.77-7.87 (4H, m),8.25-8.29 (1H, m), 9.08 (2H, br).

Example 1411-(1-{[3-(Ethylsulfonyl)phenyl]sulfonyl}-5-phenyl-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride

Using1-{[3-(ethylsulfonyl)phenyl]sulfonyl}-5-phenyl-1H-pyrrole-3-carbaldehyde(348 mg), 40% methylamine methanol solution (201 mg) and sodiumborohydride (109 mg), a procedure as in Example 9 was performed.Recrystallization from a mixed solvent of ethyl acetate and ethanol gavethe title compound as colorless crystals (yield 250 mg, 64%).

¹H-NMR (CDCl₃) δ: 1.22 (3H, t, J=7.5 Hz), 2.61 (3H, s), 3.06 (2H, q,J=7.5 Hz), 4.00 (2H, s), 6.50 (1H, d, J=2.1 Hz), 7.13-7.16 (2H, m),7.29-7.41 (3H, m), 7.54-7.59 (1H, m), 7.65-7.68 (1H, m), 7.74 (1H, d,J=2.1 Hz), 7.87-7.89 (1H, m), 8.01-8.05 (1H, m), 9.80 (2H, br).

Example 1421-[1-(2,3-Dihydro-1,4-benzodioxin-6-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

Using1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde(258 mg), 40% methylamine methanol solution (163 mg) and sodiumborohydride (87 mg), a procedure as in Example 9 was performed.Recrystallization from a mixed solvent of ethyl acetate and ethanol gavethe title compound as colorless crystals (yield 130 mg, 44%).

¹H-NMR (CDCl₃) δ: 2.55 (3H, s), 3.97 (2H, s), 4.19-4.28 (4H, m), 6.50(1H, d, J=1.8 Hz), 6.71-6.85 (3H, m), 7.17-7.35 (4H, m), 7.57 (1H, d,J=1.8 Hz), 9.82 (1H, br), 1H not detected.

Example 1432-({4-[(Methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzonitrilehydrochloride

Using 2-[(4-formyl-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzonitrile (253mg), 40% methylamine methanol solution (175 mg) and sodium borohydride(95 mg), a procedure as in Example 9 was performed. Recrystallizationfrom a mixed solvent of ethyl acetate and ethanol gave the titlecompound as colorless crystals (yield 112 mg, 38%).

¹H-NMR (CDCl₃) δ: 2.64 (3H, s), 4.04 (2H, s), 6.67 (1H, d, J=1.8 Hz),7.03-7.06 (2H, m), 7.13-7.18 (2H, m), 7.25-7.37 (3H, m), 7.56-7.60 (1H,m), 7.70-7.73 (1H, m), 7.80 (1H, d, J=1.8 Hz), 9.84 (1H, br), 1H notdetected.

Example 1444-({4-[(Methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzonitrilehydrochloride

Using 4-[(4-formyl-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzonitrile (303mg), 40% methylamine methanol solution (210 mg) and sodium borohydride(113 mg), a procedure as in Example 9 was performed. Recrystallizationfrom a mixed solvent of ethyl acetate and ethanol gave the titlecompound as colorless crystals (yield 36 mg, 10%).

¹H-NMR (CDCl₃) δ: 2.62 (3H, s), 4.01 (2H, s), 6.46 (1H, d, J=2.1 Hz),7.11-7.14 (2H, m), 7.27-7.32 (2H, m), 7.37-7.41 (1H, m), 7.47-7.50 (2H,m), 7.59-7.62 (2H, m), 7.73 (1H, d, J=2.1 Hz), 9.90 (1H, br), 1H notdetected.

Example 145 Methyl2-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzoate

Methyl 2-[(4-formyl-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoate (664 mg)was dissolved in methanol (10 mL), 40% methylamine methanol solution(419 mg) was added at room temperature, and the mixture was stirred for30 min. To the reaction mixture was added sodium borohydride (227 mg) at0° C., the mixture was stirred for 1 hr. Water was added, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby basic silica gel column chromatography (eluent: hexane-ethylacetate=1:1→0:1) to give the title compound as a pale-yellow oil (yield472 mg, 68%).

¹H-NMR (CDCl₃) δ: 2.48 (3H, s), 3.64 (2H, s), 3.89 (3H, s), 6.22 (1H, d,J=1.8 Hz), 7.00 (1H, d, J=8.1 Hz), 7.18-7.35 (7H, m), 7.50-7.52 (2H, m).

Example 146 Methyl2-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzoatehydrochloride

To a solution (1 mL) of methyl2-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzoate(105 mg) in ethyl acetate was added 4 mol/L hydrogen chloride-ethylacetate solution (0.5 mL) at room temperature. The solvent wasevaporated under reduced pressure, and the residue was crystallized from2-propanol and isopropyl ether. The obtained crystals wererecrystallized from a mixed solvent of ethyl acetate and ethanol to givethe title compound as colorless crystals (yield 68 mg, 60%).

¹H-NMR (CDCl₃) δ: 2.62 (3H, s), 3.87 (3H, s), 4.03 (2H, s), 6.56 (1H, d,J=2.1 Hz), 7.04 (1H, d, J=7.8 Hz), 7.11-7.33 (6H, m), 7.50-7.52 (2H, m),7.57 (1H, d, J=2.1 Hz), 9.82 (1H, br), 1H not detected.

Example 147 Methyl3-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzoate

Using methyl 3-[(4-formyl-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoate(1.32 g), 40% methylamine methanol solution (416 mg) and sodiumborohydride (100 mg), a procedure as in Reference Example 145 wasperformed to give the title compound as a pale-yellow oil (yield 668 mg,49%).

¹H-NMR (CDCl₃) δ: 2.43 (3H, s), 3.59 (2H, s), 3.91 (3H, s), 6.15 (1H, d,J=1.8 Hz), 7.20-7.41 (7H, m), 7.48-7.52 (1H, m), 7.97-7.98 (1H, m),8.13-8.16 (1H, m), 1H not detected.

Example 148 Methyl3-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzoatehydrochloride

Using methyl3-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzoate(91 mg), a procedure as in Example 146 was performed to give the titlecompound as colorless crystals (yield 58 mg, 58%).

¹H-NMR (CDCl₃) δ: 2.56 (3H, s), 3.90 (3H, s), 3.98 (2H, s), 6.50 (1H, d,J=1.8 Hz), 7.11-7.14 (2H, m), 7.22-7.28 (2H, m), 7.32-7.43 (2H, m),7.51-7.55 (1H, m), 7.66 (1H, d, J=1.8 Hz), 7.92-7.93 (1H, m), 8.13-8.17(1H, m), 2H not detected.

Example 1492-Chloro-4-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzonitrilehydrochloride

Using2-chloro-4-[(4-formyl-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzonitrile (248mg), 40% methylamine methanol solution (1.4 mL) and sodium borohydride(28.9 mg), a procedure as in Example 9 was performed to give the titlecompound as white crystals (yield 67.8 mg, 24%).

¹H-NMR (CDCl₃) δ: 2.64 (3H, brs), 4.01 (2H, brs), 6.49 (1H, d, J=1.8Hz), 7.14-7.16 (2H, m), 7.31-7.36 (3H, m), 7.41-7.47 (2H, m), 7.64-7.67(1H, m), 7.72 (1H, brs), 9.95 (2H, brs).

Example 150[1-(1,3-Benzothiazol-6-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]-N-methylmethanamineoxalic acid salt

Using1-(1,3-benzothiazol-6-ylsulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde(247 mg), 40% methylamine methanol solution (0.7 mL) and sodiumborohydride (31.3 mg), a procedure as in Example 126 was performed togive free base of the title compound as a yellow oil. To a solution (3mL) of the obtained free base in ethanol was added oxalic acid (10 mg),and the reaction mixture was heated until it became uniform. Thereaction mixture was cooled to room temperature, and concentrated underreduced pressure. The residue was recrystallized from ethanol to givethe title compound as white crystals (yield 20.3 mg, 11%).

¹H-NMR (DMSO-d₆) δ: 2.53 (3H, s), 3.99 (2H, s), 6.36 (1H, d, J=2.1 Hz),7.08-8.10 (2H, m), 7.29-7.34 (2H, m), 7.39-7.41 (2H, m), 7.45-7.48 (1H,m), 7.74 (1H, s), 8.18 (1H, d, J=8.4 Hz), 8.30 (1H, d, J=2.1 Hz), 9.69(1H, s), 3H not detected.

Example 1511-{1-[(1,1-Dioxido-2,3-dihydro-1-benzothien-6-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanamine

Using1-[(1,1-dioxido-2,3-dihydro-1-benzothiophen-6-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde(114 mg), 40% methylamine methanol solution (0.3 mL) and sodiumborohydride (10.8 mg), a procedure as in Example 126 was performed togive the title compound as a white solid (yield 76.3 mg, 65%).

¹H-NMR (CDCl₃) δ: 2.45 (3H, s), 3.36-3.40 (2H, m), 3.48-3.53 (2H, m),3.59 (2H, s), 6.18 (1H, d, J=1.8 Hz), 7.24-7.41 (7H, m), 7.50-7.53 (1H,m), 7.66-7.67 (1H, m), 1H not detected.

Example 1521-[1-(1-Benzothien-2-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

1-(1-Benzothien-2-ylsulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde (180mg) was dissolved in methanol (20 mL), 40% methylamine methanol solution(190 mg) was added at room temperature, and the mixture was stirred for30 min. Sodium borohydride (56 mg) was added at room temperature, andthe mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (20 mL)was added, and the mixture was stirred for 5 min. The reaction mixturewas alkalized with a saturated aqueous sodium hydrogencarbonate solutionand extracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by basic silica gel columnchromatography (eluent: hexane-ethyl acetate=3:7→0:1), and dissolved inethyl acetate (5 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution(1 mL) was added, and the mixture was concentrated under reducedpressure. The residue was crystallized from ethyl acetate to give thetitle compound as colorless crystals (yield 126 mg, 61%).

¹H-NMR (DMSO-d₆) δ: 2.49 (3H, s), 3.99 (2H, s), 6.54 (1H, d, J=1.8 Hz),7.23-7.26 (2H, m), 7.34-7.62 (5H, m), 7.75 (1H, d, J=1.8 Hz), 7.77-7.78(1H, m), 7.96-7.98 (1H, m), 8.08-8.11 (1H, m), 9.23 (2H, br).

Example 153N-Methyl-1-(1-{[4-(methylsulfonyl)phenyl]sulfonyl}-5-phenyl-1H-pyrrol-3-yl)methanaminehydrochloride

1-{[4-(Methylsulfonyl)phenyl]sulfonyl}-5-phenyl-1H-pyrrole-3-carbaldehyde(60 mg) was dissolved in methanol (20 mL), 40% methylamine methanolsolution (120 mg) was added at room temperature, and the mixture wasstirred for 30 min. Sodium borohydride (30 mg) was added at roomtemperature, and the mixture was stirred for 10 min. 1 mol/LHydrochloric acid (20 mL) was added, and the mixture was stirred for 5min. The reaction mixture was alkalized with a saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was purified bybasic silica gel column chromatography (eluent: ethylacetate-methanol=1:0→7:3), and dissolved in methanol (5 mL). A 4 mol/Lhydrogen chloride-ethyl acetate solution (1 mL) was added, and themixture was concentrated under reduced pressure. The residue wascrystallized from ethyl acetate to give the title compound as colorlesscrystals (yield 42 mg, 62%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 3.30 (3H, s), 3.99 (2H, s), 6.50 (1H,d, J=1.8 Hz), 7.13-7.16 (2H, m), 7.34-7.47 (3H, m), 7.63-7.68 (2H, m),7.78 (1H, d, J=1.8 Hz), 8.03-8.08 (2H, m), 9.11 (2H, br).

Example 1541-[3-({4-[(Methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)phenyl]ethanone0.5 oxalic acid salt

1-[(3-Acetylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde (200 mg)was dissolved in methanol (30 mL), methylamine hydrochloride (192 mg)was added at room temperature and the mixture was stirred for 30 min.Sodium triacetoxyborohydride (360 mg) was added at room temperature andthe mixture was stirred for 2 hr. Saturated aqueous sodiumhydrogencarbonate solution was added to the reaction mixture and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by basic silica gelcolumn chromatography (eluent: ethyl acetate-methanol=1:0→7:3), anddissolved in ethyl acetate (10 mL). Oxalic acid (50 mg) was added andthe mixture was stirred for 15 min. The crystallized crystals werecollected by filtration to give the title compound as colorless crystals(yield 6.7 mg, 3%).

MS (ESI+): 369 (M+H)

Example 155N-Methyl-1-{1-[(3-nitrophenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methanaminehydrochloride

1-[(3-Nitrophenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde (750 mg)was dissolved in methanol (50 mL), 40% methylamine methanol solution(1.64 g) was added at room temperature, and the mixture was stirred for30 min. Sodium borohydride (240 mg) was added at room temperature, andthe mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (100 mL)was added, and the mixture was stirred for 5 min. The reaction mixturewas alkalized with a saturated aqueous sodium hydrogencarbonate solutionand extracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate. The mixture was concentratedunder reduced pressure to give a free base of the title compound as acrude product. A part (50 mg) of the obtained crude free base wasdissolved in methanol (10 mL), a 4 mol/L hydrogen chloride-ethyl acetatesolution (1 mL) was added, and the mixture was concentrated underreduced pressure. The residue was crystallized from ethyl acetate togive the title compound as colorless crystals (yield 43 mg, 5%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, t, J=5.1 Hz), 3.98 (2H, t, J=5.1 Hz), 6.52(1H, d, J=1.8 Hz), 7.12-7.16 (2H, m), 7.33-7.46 (3H, m), 7.80-8.01 (4H,m), 8.51-8.55 (1H, m), 9.21 (2H, br).

Example 156N-Methyl-1-[5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanaminedihydrochloride

5-Phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (230 mg) wasdissolved in absolute tetrahydrofuran (10 mL), a 2 mol/L solution (1 mL)of methylamine in tetrahydrofuran was added, and the mixture was stirredat room temperature for 2 hr. The reaction mixture was added to asolution of sodium borohydride (76 mg) in methanol (5 mL), and themixture was stirred at the same temperature for 20 min. The reactionmixture was diluted with ethyl acetate, washed successively withsaturated aqueous sodium hydrogencarbonate solution, water and saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: ethyl acetate-methanol=1:0→1:1), andfurther purified by HPLC (ODS, 0.1% trifluoroacetic acid containingwater-0.1% trifluoroacetic acid containing acetonitrile=97:3→0.1%trifluoroacetic acid containing acetonitrile) to give trifluoroacetateof the title compound. The obtained trifluoroacetate was neutralizedwith saturated aqueous sodium hydrogencarbonate solution, extracted withethyl acetate, washed successively with saturated aqueous sodiumhydrogencarbonate solution, water and saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was dissolved in ethyl acetate (5 mL). A 4 mol/Lhydrogen chloride-ethyl acetate solution (1 mL) and ethanol (5 mL) wereadded, and the mixture was concentrated under reduced pressure. Theresidue was crystallized from ethyl acetate-ethanol to give the titlecompound (yield 85 mg, 29%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 3.97-4.00 (2H, s), 6.50 (1H, s),7.14-7.16 (2H, m), 7.35-7.45 (3H, m), 7.62-7.70 (1H, m), 7.78-7.83 (2H,m), 8.47-8.48 (1H, m), 8.84-8.86 (1H, m), 9.08 (2H, br), 1H notdetected.

Example 1571-{1-[(6-Methoxypyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanaminehydrochloride

1-[(6-Methoxypyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde(59 mg) was dissolved in absolute tetrahydrofuran (5 mL), a 2 mol/Lsolution (0.25 mL) of methylamine in tetrahydrofuran was added, and themixture was stirred at room temperature for 3 hr. The reaction mixturewas added to a solution of sodium borohydride (19 mg) in methanol (2mL), and the mixture was stirred at the same temperature for 20 min. Thereaction mixture was diluted with ethyl acetate, washed successivelywith water and saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The residuewas purified by silica gel column chromatography (eluent: ethylacetate-methanol=1:0→1:1) to give a free base (48 mg) of the titlecompound. The obtained free base was dissolved in ethyl acetate (2 mL),a 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL) was added, andthe mixture was stood at room temperature for 30 min. The precipitatedcrystals were collected by filtration, and washed with ethyl acetate togive the title compound (yield 39 mg, 58%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 3.90 (3H, s), 3.98 (2H, s), 6.45 (1H,s), 6.91-6.94 (1H, m), 7.16-7.18 (2H, m), 7.36-7.45 (3H, m), 7.59-7.63(1H, m), 7.72 (1H, s), 8.09-8.10 (1H, m), 8.91 (2H, br).

Example 158N-Methyl-1-[1-(4-methylaminopyridin-3-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]methanaminedihydrochloride

Using 1-(6-chloro-3-pyridinesulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde(100 mg), a procedure as in Example 157 was performed to give the titlecompound (yield 58 mg, 47%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 2.78 (3H, s), 3.95-3.99 (2H, m),6.39-6.42 (2H, m), 7.20-7.23 (3H, m), 7.35-7.43 (3H, m), 7.63 (1H, s),7.82-7.85 (2H, m), 9.00 (2H, br), 1H not detected.

Example 159N-Methyl-1-[1-(2-methylaminopyridin-3-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]methanaminedihydrochloride

1-(2-Chloropyridin-3-ylsulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde (173mg) was dissolved in tetrahydrofuran (10 mL), a 2 mol/L solution (1.25mL) of methylamine in tetrahydrofuran was added, and the mixture wasstirred at room temperature for 12 hr. The reaction mixture was added toa solution (2 mL) of sodium borohydride (76 mg) in methanol, and themixture was stirred at room temperature for 20 min. Saturated aqueoussodium hydrogencarbonate solution was added, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent: ethyl acetate→ethyl acetate-methanol=1:4) togive a free base of the title compound. A 4 mol/L hydrogenchloride-ethyl acetate solution (1 mL) was added to a solution (3 mL) ofthe obtained free base in ethanol. The solvent was evaporated underreduced pressure, and the residue was recrystallized from ethanol togive the title compound (yield 126 mg, 59%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 2.77 (3H, d, J=4.5 Hz), 3.95-3.99 (2H,m), 4.80 (1H, br), 6.28-6.30 (1H, m), 6.41-6.47 (2H, m), 7.10-7.19 (3H,m), 7.32-7.44 (3H, m), 7.88 (1H, s), 8.25-8.27 (1H, m), 9.19 (2H, br).

Example 160N-Methyl-1-[1-(2-methylaminopyrimidin-5-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]methanaminehydrochloride

Using1-(2-chloropyrimidin-5-ylsulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde(100 mg), a procedure as in Example 157 was performed to give the titlecompound (yield 64 mg, 57%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 2.80-2.82 (3H, s), 3.98 (2H, s), 6.47(1H, s), 7.23-7.26 (2H, m), 7.39-7.43 (3H, m), 7.66-7.67 (1H, m),7.96-7.97 (1H, m), 8.11-8.12 (1H, m), 8.48-8.52 (1H, m), 8.97 (2H, br).

Example 1611-[5-(2-Fluorophenyl)-1-{[3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

5-(2-Fluorophenyl)-1-{[3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrole-3-carbaldehyde(550 mg) was dissolved in methanol (55 mL), 40% methylamine methanolsolution (1.05 g) was added at room temperature, and the mixture wasstirred for 30 min. Sodium borohydride (154 mg) was added at roomtemperature, and the mixture was stirred for 10 min. 1 mol/LHydrochloric acid (100 mL) was added, and the mixture was stirred for 5min. The reaction mixture was alkalized with a saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was dissolved inmethanol (10 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution (2mL) was added, and the mixture was concentrated under reduced pressure.The residue was crystallized from ethyl acetate to give the titlecompound as colorless crystals (yield 400 mg, 65%).

¹H-NMR (DMSO-d₆) δ: 2.48 (3H, t, J=5.5 Hz), 3.30 (3H, s), 3.98 (2H, t,J=5.5 Hz), 6.61 (1H, d, J=1.7 Hz), 7.07-7.12 (1H, m), 7.20-7.26 (2H, m),7.50-7.57 (1H, m), 7.86-7.90 (4H, m), 8.29-8.33 (1H, m), 9.31 (2H, br).

Example 1621-[1-{[3-(Ethylsulfonyl)phenyl]sulfonyl}-5-(2-fluorophenyl)-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

Using1-{[3-(ethylsulfonyl)phenyl]sulfonyl}-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde(181 mg), 40% methylamine methanol solution (100 mg) and sodiumborohydride (54 mg), a procedure as in Example 9 was performed.Recrystallization from a mixed solvent of ethyl acetate and ethanol gavethe title compound as colorless crystals (yield 107 mg, 53%).

¹H-NMR (DMSO-d₆) δ: 1.08 (3H, t, J=7.5 Hz), 2.49-2.51 (3H, m), 3.37 (2H,q, J=7.5 Hz), 3.98 (2H, brs), 6.57 (1H, d, J=2.1 Hz), 7.07-7.12 (1H, m),7.19-7.25 (2H, m), 7.50-7.55 (1H, m), 7.81-7.90 (4H, m), 8.24-8.28 (1H,m), 9.06 (2H, br).

Example 1632-{[2-(2-Fluorophenyl)-4-[(methylamino)methyl]-1H-pyrrol-1-yl]sulfonyl}benzonitrilehydrochloride

2-{[2-(2-Fluorophenyl)-4-formyl-1H-pyrrol-1-yl]sulfonyl}benzonitrile(370 mg) was dissolved in methanol (20 mL), 40% methylamine methanolsolution (811 mg) was added at room temperature, and the mixture wasstirred for 30 min. Sodium borohydride (120 mg) was added at roomtemperature, and the mixture was stirred for 10 min. 1 mol/LHydrochloric acid (50 mL) was added, and the mixture was stirred for 5min. The reaction mixture was alkalized with a saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was purified bybasic silica gel column chromatography (eluent: ethylacetate-methanol=1:0→7:3), and dissolved in methanol (10 mL). A 4 mol/Lhydrogen chloride-ethyl acetate solution (2 mL) was added, and themixture was concentrated under reduced pressure. The residue wascrystallized from ethyl acetate to give the title compound as colorlesscrystals (yield 280 mg, 66%).

¹H-NMR (DMSO-d₆) δ: 2.52 (3H, s), 4.04 (2H, s), 6.65 (1H, d, J=1.8 Hz),7.03-7.18 (3H, m), 7.35-7.38 (1H, m), 7.45-7.53 (1H, m), 7.74-7.80 (1H,m), 7.87 (1H, d, J=1.8 Hz), 7.90-7.95 (1H, m), 8.14-8.17 (1H, m), 9.28(2H, br).

Example 1644-{[2-(2-Fluorophenyl)-4-[(methylamino)methyl]-1H-pyrrol-1-yl]sulfonyl}benzonitrilehydrochloride

4-{[2-(2-Fluorophenyl)-4-formyl-1H-pyrrol-1-yl]sulfonyl}benzonitrile(385 mg) was dissolved in methanol (20 mL), 40% methylamine methanolsolution (844 mg) was added at room temperature, and the mixture wasstirred for 30 min. Sodium borohydride (124 mg) was added at roomtemperature, and the mixture was stirred for 10 min. 1 mol/LHydrochloric acid (50 mL) was added, and the mixture was stirred for 5min. The reaction mixture was alkalized with a saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas purified with saturated brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was washed withbasic silica gel column chromatography (eluent: ethylacetate-methanol=1:0→7:3), and dissolved in methanol (10 mL). A 4 mol/Lhydrogen chloride-ethyl acetate solution (2 mL) was added, and themixture was concentrated under reduced pressure. The residue wascrystallized from ethyl acetate to give the title compound as colorlesscrystals (yield 274 mg, 62%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 3.99 (2H, s), 6.60 (1H, d, J=1.7 Hz),7.04-7.10 (1H, m), 7.20-7.27 (2H, m), 7.50-7.57 (1H, m), 7.62-7.66 (2H,m), 7.84 (1H, d, J=1.7 Hz), 8.05-8.09 (2H, m), 9.25 (2H, br).

Example 1651-{5-(2-Fluorophenyl)-1-[(2-fluorophenyl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanaminehydrochloride

5-(2-Fluorophenyl)-1-[(2-fluorophenyl)sulfonyl]-1H-pyrrole-3-carbaldehyde(330 mg) was dissolved in methanol (33 mL), 40% methylamine methanolsolution (370 mg) was added at room temperature, and the mixture wasstirred for 30 min. Sodium borohydride (108 mg) was added at roomtemperature, and the mixture was stirred for 10 min. 1 mol/LHydrochloric acid (50 mL) was added, and the mixture was stirred for 5min. The reaction mixture was alkalized with a saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was purified bybasic silica gel column chromatography (eluent: ethylacetate-methanol=1:0→7:3), and dissolved in methanol (5 mL). A 4 mol/Lhydrogen chloride-ethyl acetate solution (2 mL) was added, and themixture was concentrated under reduced pressure. The residue wascrystallized from ethyl acetate to give the title compound as colorlesscrystals (yield 266 mg, 70%).

¹H-NMR (DMSO-d₆) δ: 2.51 (3H, s), 4.02 (2H, s), 6.61 (1H, d, J=1.8 Hz),7.01-7.30 (5H, m), 7.44-7.52 (2H, m), 7.79-7.85 (2H, m), 9.28 (2H, br).

Example 1661-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminefumarate

5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(1.52 g) was dissolved in methanol (30 mL), 40% methylamine methanolsolution (3.57 g) was added at room temperature and the mixture wasstirred for 30 min. Sodium borohydride (523 mg) was added at roomtemperature and the mixture was stirred for 10 min. 1 mol/L Hydrochloricacid (50 mL) was added and the mixture was stirred for 5 min. Thereaction mixture was basified with saturated aqueous sodiumhydrogencarbonate solution, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by basic silica gel column chromatography (eluent:ethyl acetate-methanol=1:0→7:3) to give a free base of the titlecompound as a pale-yellow oil (yield 1.30 g). The obtained free base(750 mg) was dissolved in ethyl acetate (30 mL), and a solution offumaric acid (278 mg) in methanol (3 mL) was added dropwise at roomtemperature. After stirring for 30 min, the obtained crystals werecollected by filtration, and washed with ethyl acetate to give the titlecompound as colorless crystals (yield 912 mg, 74%).

¹H-NMR (DMSO-d₆) δ: 2.43 (3H, s), 3.87 (2H, s), 6.47 (2H, s), 6.49 (1H,d, J=1.8 Hz), 7.07-7.13 (1H, m), 7.19-7.26 (2H, m), 7.49-7.56 (1H, m),7.59-7.64 (1H, m), 7.74 (1H, d, J=1.8 Hz), 7.86-7.90 (1H, m), 8.56-8.57(1H, m), 8.87-8.89 (1H, m), 3H not detected.

Example 167N-Methyl-1-(1-{[3-(methylsulfonyl)phenyl]sulfonyl}-5-[2-(trifluoromethyl)phenyl]-1H-pyrrol-3-yl)methanaminehydrochloride

1-{[3-(Methylsulfonyl)phenyl]sulfonyl}-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbaldehyde(300 mg) was dissolved in methanol (30 mL), 40% methylamine methanolsolution (510 mg) was added at room temperature, and the mixture wasstirred for 30 min. Sodium borohydride (75 mg) was added at roomtemperature, and the mixture was stirred for 10 min. 1 mol/LHydrochloric acid (30 mL) was added, and the mixture was stirred for 5min. The reaction mixture was alkalized with a saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was purified bybasic silica gel column chromatography (eluent: ethylacetate-methanol=1:0→7:3), and dissolved in methanol (5 mL). A 4 mol/Lhydrogen chloride-ethyl acetate solution (2 mL) was added, and themixture was concentrated under reduced pressure. The residue wascrystallized from ethyl acetate to give the title compound as colorlesscrystals (yield 214 mg, 64%).

¹H-NMR (DMSO-d₆) δ: 2.46-2.50 (3H, m), 3.30 (3H, s), 3.99-4.03 (2H, m),6.54 (1H, d, J=1.7 Hz), 7.16-7.18 (1H, m), 7.64-7.96 (7H, m), 8.32-8.35(1H, m), 9.20 (2H, br).

Example 168N-Methyl-1-{1-(pyridin-3-ylsulfonyl)-5-[2-(trifluoromethyl)phenyl]-1H-pyrrol-3-yl}methanaminedihydrochloride

1-(Pyridin-3-ylsulfonyl)-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbaldehyde(340 mg) was dissolved in methanol (34 mL), 40% methylamine methanolsolution (695 mg) was added at room temperature and the mixture wasstirred for 30 min. sodium borohydride (102 mg) was added at roomtemperature and the mixture was stirred for 10 min. 1 mol/L Hydrochloricacid (10 mL) was added and the mixture was stirred for 5 min. Thereaction mixture was basified with saturated aqueous sodiumhydrogencarbonate solution, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by basic silica gel column chromatography (eluent:ethyl acetate-methanol=1:0→7:3), and dissolved in ethyl acetate (5 mL).A 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, andthe mixture was concentrated under reduced pressure. The residue wascrystallized from ethyl acetate to give the title compound as pale-redcrystals (yield 288 mg, 69%).

¹H-NMR (DMSO-d₆) δ: 2.47 (3H, t, J=5.5 Hz), 4.00 (2H, t, J=5.5 Hz), 6.60(1H, d, J=1.8 Hz), 7.18-7.21 (1H, m), 7.63-7.81 (4H, m), 7.91-8.00 (2H,m), 8.58 (1H, d, J=1.8 Hz), 8.90-8.92 (1H, m), 9.48-9.57 (2H, m), 1H notdetected.

Example 169N-Methyl-1-[5-(2-methylphenyl)-1-{[3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrol-3-yl]methanaminehydrochloride

5-(2-Methylphenyl)-1-{[3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrole-3-carbaldehyde(250 mg) was dissolved in methanol (25 mL), 40% methylamine methanolsolution (482 mg) was added at room temperature, and the mixture wasstirred for 30 min. Sodium borohydride (71 mg) was added at roomtemperature, and the mixture was stirred for 10 min. 1 mol/LHydrochloric acid (30 mL) was added, and the mixture was stirred for 5min. The reaction mixture was alkalized with a saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was purified bybasic silica gel column chromatography (eluent: ethylacetate-methanol=1:0→7:3), and dissolved in methanol (5 mL). To thesolution was added a 4 mol/L hydrogen chloride-ethyl acetate solution (2mL), and the mixture was concentrated under reduced pressure. Theresidue was crystallized from ethyl acetate to give the title compoundas colorless crystals (yield 156 mg, 55%).

¹H-NMR (DMSO-d₆) δ: 1.82 (3H, s), 2.49 (3H, s), 3.29 (3H, s), 4.00 (2H,s), 6.45 (1H, d, J=1.8 Hz), 6.83-6.85 (1H, m), 7.11-7.21 (2H, m),7.31-7.37 (1H, m), 7.78-7.89 (4H, m), 8.29-8.33 (1H, m), 9.31 (2H, br).

Example 170N-Methyl-1-[1-(phenylsulfonyl)-5-(pyridin-2-yl)-1H-pyrrol-3-yl]methanamineoxalic acid salt

1-(Phenylsulfonyl)-5-(pyridin-2-yl)-1H-pyrrole-3-carbaldehyde (78 mg)was dissolved in methanol (10 mL), 40% methylamine methanol solution(100 mg) was added at room temperature, and the mixture was stirred for30 min. Sodium borohydride (29 mg) was added at room temperature, andthe mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (20 mL)was added, and the mixture was stirred for 5 min. The reaction mixturewas alkalized with a saturated aqueous sodium hydrogencarbonate solutionand extracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified by basic silica gel columnchromatography (eluent: ethyl acetate-methanol=1:0→7:3) and dissolved inethyl acetate (10 mL). To the solution was added oxalic acid (50 mg) andthe mixture was stirred for 15 min. The crystallized crystals werecollected by filtration to give the title compound as colorless crystals(yield 47 mg, 45%).

¹H-NMR (DMSO-d₆) δ: 2.55 (3H, s), 4.02 (2H, s), 6.70 (1H, d, J=1.8 Hz),7.33-7.38 (1H, m), 7.51-7.54 (1H, m), 7.63-7.68 (2H, m), 7.74-7.91 (5H,m), 8.44-8.46 (1H, m).

Example 1711-{1-[(3,4-Difluorophenyl)sulfonyl]-5-(pyridin-2-yl)-1H-pyrrol-3-yl}-N-methylmethanaminedihydrochloride

1-[(3,4-Difluorophenyl)sulfonyl]-5-(pyridin-2-yl)-1H-pyrrole-3-carbaldehyde(100 mg) was dissolved in methanol (20 mL), 40% methylamine methanolsolution (112 mg) was added at room temperature, and the mixture wasstirred for 30 min. Sodium borohydride (33 mg) was added at roomtemperature, and the mixture was stirred for 10 min. 1 mol/LHydrochloric acid (20 mL) was added, and the mixture was stirred for 5min. The reaction mixture was alkalized with a saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was purified bybasic silica gel column chromatography (eluent: ethyl acetate), anddissolved in methanol (5 mL). A 4 mol/L hydrogen chloride-ethyl acetatesolution (1 mL) was added, and the mixture was concentrated underreduced pressure. The residue was crystallized from a mixed solvent(1:10) of methanol-tetrahydrofuran to give the title compound ascolorless crystals (yield 89 mg, 71%).

¹H-NMR (DMSO-d₆) δ: 2.53 (3H, t, J=5.5 Hz), 4.00 (2H, t, J=5.5 Hz), 6.85(1H, d, J=1.8 Hz), 7.39-7.43 (1H, m), 7.56-7.58 (1H, m), 7.73-7.94 (4H,m), 8.09-8.15 (1H, m), 8.48-8.50 (1H, m), 9.22 (2H, br).

Example 1721-[1-(2,3-Dihydro-1,4-benzodioxin-5-ylsulfonyl)-4-methyl-5-phenyl-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

Using1-(2,3-dihydro-1,4-benzodioxin-5-ylsulfonyl)-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde(295 mg), 40% methylamine methanol solution (179 mg) and sodiumborohydride (87 mg), a procedure as in Example 9 was performed.Recrystallization from a mixed solvent of ethyl acetate and ethanol gavethe title compound as colorless crystals (yield 159 mg, 48%).

¹H-NMR (CDCl₃) δ: 1.90 (3H, s), 2.65 (3H, s), 4.02 (2H, s), 4.20-4.29(4H, m), 6.73-6.76 (1H, m), 6.84-6.88 (2H, m), 7.04-7.08 (2H, m),7.28-7.40 (3H, m), 7.72 (1H, s), 9.79 (2H, br).

Example 1731-{1-[(2,5-Dimethoxyphenyl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanaminehydrochloride

Using1-[(2,5-dimethoxyphenyl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde(330 mg), 40% methylamine methanol solution (199 mg) and sodiumborohydride (97 mg), a procedure as in Example 9 was performed.Recrystallization from a mixed solvent of ethyl acetate and ethanol gavethe title compound as colorless crystals (yield 201 mg, 54%).

¹H-NMR (CDCl₃) δ: 1.90 (3H, s), 2.70 (3H, s), 3.51 (3H, s), 3.79 (3H,s), 4.07 (2H, s), 6.57 (1H, d, J=3.3 Hz), 6.82-6.89 (3H, m), 6.99-7.03(1H, m), 7.15-7.30 (3H, m), 7.78 (1H, s), 9.79 (1H, br), 1H notdetected.

Example 1741-[1-(2,3-Dihydro-1,4-benzodioxin-6-ylsulfonyl)-4-methyl-5-phenyl-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

Using1-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde(391 mg), 40% methylamine methanol solution (233 mg) and sodiumborohydride (126 mg), a procedure as in Example 9 was performed.Recrystallization from a mixed solvent of ethyl acetate and ethanol gavethe title compound as colorless crystals (yield 194 mg, 45%).

¹H-NMR (CDCl₃) δ: 1.90 (3H, s), 2.64 (3H, s), 4.02 (2H, s), 4.20-4.28(4H, m), 6.73-6.76 (1H, m), 6.84-6.88 (2H, m), 7.04-7.07 (2H, m),7.19-7.40 (3H, m), 7.71 (1H, m), 9.75 (1H, br), 1H not detected.

Example 1751-(1-{[3-(Methylsulfonyl)phenyl]sulfonyl}-4-methyl-5-phenyl-1H-pyrrol-3-yl)-N-methylmethanaminehydrochloride

Using4-methyl-1-{[3-(methylsulfonyl)phenyl]sulfonyl}-5-phenyl-1H-pyrrole-3-carbaldehyde(191 mg), a procedure as in Example 134 was performed to give the titlecompound as a solid (yield 159 mg, 74%).

¹H-NMR (DMSO-d₆) δ: 1.78 (3H, s), 2.56 (3H, s), 3.28 (3H, s), 3.99 (2H,s), 6.99-7.03 (2H, m), 7.36-7.44 (3H, m), 7.75-7.88 (4H, m), 8.24-8.29(1H, m), 8.92 (2H, br).

Example 176N-Methyl-1-{4-methyl-5-phenyl-1-(3-thienylsulfonyl)-1H-pyrrol-3-yl}methanaminehydrochloride

Using 4-methyl-5-phenyl-1-(3-thienylsulfonyl)-1H-pyrrole-3-carbaldehyde(290 mg), a procedure as in synthesis of Example 134 was performed togive the title compound as a solid (yield 208 mg, 62%).

¹H-NMR (DMSO-d₆) δ: 1.79 (3H, s), 2.57 (3H, s), 3.98 (2H, s), 6.98-7.04(3H, m), 7.35-7.43 (3H, m), 7.69-7.73 (2H, m), 7.73-7.90 (1H, m), 8.93(2H, br).

Example 177N-Methyl-1-[4-methyl-1-(pyridin-3-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]methanaminedihydrochloride

Using4-methyl-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(171 mg), a procedure as in Example 157 was performed to give the titlecompound (yield 110 mg, 50%).

¹H-NMR (DMSO-d₆) δ: 1.79 (3H, s), 2.57 (3H, s), 3.96-4.00 (2H, m),6.98-7.01 (2H, m), 7.36-7.43 (3H, m), 7.55-7.60 (1H, m), 7.79-7.82 (2H,m), 8.43-8.44 (1H, m), 8.84-8.86 (1H, m), 9.13 (2H, br), 1H notdetected.

Example 178N-Methyl-1-[4-methyl-1-(pyridin-2-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]methanaminehydrochloride

4-Methyl-5-phenyl-1-(pyridin-2-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(262 mg) was dissolved in tetrahydrofuran (10 mL), a 2 mol/L solution(1.0 mL) of methylamine in tetrahydrofuran was added, and the mixturewas stirred at room temperature for 4 hr. The reaction mixture was addedto a solution (5 mL) of sodium borohydride (76 mg) in methanol, and themixture was stirred at room temperature for 20 min. Water was added, andthe mixture was extracted with ethyl acetate. The extract was washedwith water and saturated brine, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (eluent: ethylacetate-methanol=1:0→1:1), and further purified by HPLC (ODS, 0.1%trifluoroacetic acid containing water-0.1% trifluoroacetic acidcontaining acetonitrile=9:1→0.1% trifluoroacetic acid containingacetonitrile) to give trifluoroacetate of the title compound. Theobtained trifluoroacetate was neutralized with saturated aqueous sodiumhydrogencarbonate solution, extracted with ethyl acetate, washedsuccessively with saturated aqueous sodium hydrogencarbonate solution,water and saturated brine and dried over anhydrous magnesium sulfate,and the solvent was evaporated under reduced pressure. The residue wasdissolved in ethyl acetate (3 mL), and a 4 mol/L hydrogen chloride-ethylacetate solution (2 mL) was added, and the mixture was stood at roomtemperature for 30 min. The precipitated product was collected byfiltration, and washed with ethyl acetate to give the title compound(yield 141 mg, 47%).

¹H-NMR (DMSO-d₆) δ: 1.79 (3H, s), 2.59 (3H, s), 4.01 (2H, s), 6.88-6.90(2H, m), 7.27-7.45 (4H, m), 7.71-7.74 (2H, m), 7.95-7.99 (1H, m),8.68-8.70 (1H, m), 8.88 (2H, br).

Example 1791-{1-[(1,2-Dimethyl-1H-imidazol-4-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanaminedihydrochloride

1-[(1,2-Dimethyl-1H-imidazol-4-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde(294 mg) was dissolved in tetrahydrofuran (5 mL), a 2 mol/L solution(1.0 mL) of methylamine in tetrahydrofuran was added, and the mixturewas stirred at room temperature for 1 hr. The mixture was heated to 40°C., and the mixture was further stirred for 4 hr. The reaction mixturewas added to a solution (5 mL) of sodium borohydride (76 mg) inmethanol, and the mixture was stirred at room temperature for 1 hr.Water was added, and the mixture was extracted with ethyl acetate. Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by basic silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→0:1) to give a free base of the title compound.To a solution (3 mL) of the obtained free base in ethyl acetate wasadded a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL). Themixture was stood at room temperature for 30 min, and the precipitatedproduct was collected by filtration and washed with ethyl acetate togive the title compound (yield 196 mg, 53%).

¹H-NMR (DMSO-d₆) δ: 1.79 (3H, s), 2.25 (3H, s), 2.60 (3H, m), 3.45 (3H,s), 3.95-3.99 (2H, m), 4.86 (1H, br), 6.99-7.01 (2H, m), 7.13 (1H, s),7.32-7.39 (3H, m), 7.59 (1H, s), 8.96 (2H, br).

Example 1801-{1-[(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanaminehydrochloride

Using1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde(378 mg), a procedure as in Example 179 was performed to give the titlecompound as a solid (yield 238 mg, 55%).

¹H-NMR (DMSO-d₆) δ: 1.67 (3H, s), 1.79 (3H, s), 2.58 (3H, s), 3.67 (3H,s), 3.99 (2H, s), 6.97-6.99 (2H, m), 7.33-7.41 (3H, m), 7.73 (1H, s),8.90 (2H, br).

Example 1811-{1-[(1,3-Dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanaminehydrochloride

Using1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde(295 mg), a free base (297 mg) of the compound of Example 180 wasobtained as an oil. The obtained oil was dissolved in toluene (10 mL)and methanol (10 mL), 10% palladium carbon (50% containing water, 30 mg)and 20% sodium ethoxide-ethanol solution (309 mg) were added, and themixture was stirred under a hydrogen atmosphere at room temperature for24 hr. The reaction mixture was filtrated, and the filtrate wasconcentrated under reduced pressure. The residue was dissolved in ethylacetate solution (5 mL), and a 4 mol/L hydrogen chloride-ethyl acetatesolution (1 mL) was added. The mixture was stood at room temperature for30 min, and the precipitated product was collected by filtration andwashed with ethyl acetate to give the title compound (yield 221 mg,72%).

¹H-NMR (DMSO-d₆) δ: 1.80 (3H, s), 1.90 (3H, s), 2.59 (3H, m), 3.63 (3H,s), 3.99 (2H, s), 6.99-7.02 (2H, m), 7.35-7.40 (3H, m), 7.51 (1H, s),7.66 (1H, s), 8.87 (2H, br).

Example 1821-{1-[(2,4-Dimethyl-1,3-thiazol-5-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanaminetrifluoroacetate

To a solution (1 ml) of1-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde(27.7 mg) in tetrahydrofuran was added a 2 mol/L solution (0.1 mL) ofmethylamine in tetrahydrofuran, and the mixture was stirred at roomtemperature for 2 hr. The reaction mixture was added to a solution (1mL) of sodium borohydride (7.6 mg) in methanol, and the mixture wasstirred at room temperature for 20 min. Water was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated aqueous sodium hydrogencarbonate solution,water and saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by HPLC(ODS, 0.1% trifluoroacetic acid containing water-0.1% trifluoroaceticacid containing acetonitrile (97:3)→0.1% trifluoroacetic acid containingacetonitrile alone), and triturated with diisopropyl ether to give thetitle compound as a solid (yield 12.1 mg, 33%).

¹H-NMR (DMSO-d₆) δ: 1.80 (3H, s), 2.06 (3H, s), 2.58 (3H, s), 2.62 (3H,s), 4.03 (2H, s), 7.05-7.07 (2H, m), 7.37-7.44 (3H, m), 7.67 (1H, s),8.62 (2H, br).

Example 183[5-(2-Fluorophenyl)-4-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

To a solution of5-(2-fluorophenyl)-4-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(382 mg) in methanol (5 mL) and tetrahydrofuran (2 mL) was added 40%methylamine methanol solution (1.1 mL), and the mixture was stirred atroom temperature for 4 hr. To the reaction mixture was added sodiumborohydride (51 mg), and the mixture was further stirred for 15 min. Thereaction mixture was concentrated under reduced pressure. Saturatedaqueous sodium hydrogencarbonate solution (50 mL) was added to theresidue, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated aqueous sodium hydrogencarbonate solution,water and saturated brine, dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby basic silica gel column chromatography (eluent: ethyl acetate) togive a free base of the title compound (yield 342 mg). To a solution ofthe obtained free base (336 mg) in ethanol (5 mL) was added a 4 mol/Lhydrogen chloride-ethyl acetate solution (5.0 mL), and the mixture wasstirred at room temperature for 30 min. The reaction mixture wasconcentrated under reduced pressure, and the residue was recrystallizedfrom ethanol to give the title compound as white crystals (yield 197 mg,46%).

¹H-NMR (DMSO-d₆) δ: 1.76 (3H, s), 2.59 (3H, t, J=5.4 Hz), 4.01 (2H, t,J=5.4 Hz), 7.03-7.08 (1H, m), 7.21-7.28 (2H, m), 7.51-7.64 (2H, m),7.82-7.86 (2H, m), 8.53 (1H, d, J=2.4 Hz), 8.80-8.89 (3H, m).

Example 184N-Methyl-[2-methyl-1-(phenylsulfonyl)-5-(3-pyridyl)-1H-pyrrol-3-yl]methanamine0.5 oxalic acid salt

To a solution of2-methyl-1-(phenylsulfonyl)-5-(3-pyridyl)-1H-pyrrole-3-carbaldehyde (276mg) in methanol (2 mL) and tetrahydrofuran (2 mL) were added 40%methylamine methanol solution (1.0 mL) and anhydrous magnesium sulfate(270 mg), and the reaction mixture was stirred at room temperature for 4hr. To the reaction mixture was added sodium borohydride (43 mg) at roomtemperature and the mixture was stirred for 30 min. The reaction mixturewas concentrated under reduced pressure, saturated aqueous sodiumhydrogencarbonate solution was added to the residue, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedaqueous sodium hydrogencarbonate solution, water and saturated brine,dried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by basic silica gelcolumn chromatography (eluent: ethyl acetate) to give a free base of thetitle compound as a yellow oil. To a solution (4 mL) of the obtainedfree base in ethanol was added a solution (2 mL) of oxalic acid (18 mg)in ethanol. The mixture was stirred at room temperature for 10 min, andconcentrated under reduced pressure. The residue was recrystallized fromethanol to give the title compound as white crystals (yield 103 mg,59%).

¹H-NMR (DMSO-d₆) δ: 2.28 (3H, s), 2.41 (3H, s), 3.64 (2H, s), 6.42 (1H,s), 7.40-7.46 (3H, m), 7.58 (2H, t, J=7.5 Hz), 7.70-7.75 (2H, m), 8.45(1H, t, J=0.9 Hz), 8.54-8.57 (1H, m), 2H not detected.

Example 185N-Methyl-[2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanamineoxalic acid salt

To a solution of2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde(386 mg) in methanol (5 mL) and tetrahydrofuran (5 mL) were added 40%methylamine methanol solution (1.5 mL) and anhydrous magnesium sulfate(319 mg), and the reaction mixture was stirred at room temperature for12 hr. To the reaction mixture was added sodium borohydride (62 mg) atroom temperature and the mixture was stirred for 30 min. The reactionmixture was concentrated under reduced pressure, saturated aqueoussodium hydrogencarbonate solution was added to the residue, and themixture was extracted with ethyl acetate. The extract was washed withsaturated aqueous sodium hydrogencarbonate solution, water and saturatedbrine, dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by basicsilica gel column chromatography (eluent: ethyl acetate) to give a freebase of the title compound as a yellow oil. To a solution (4 mL) of theobtained free base in ethanol was added a solution (2 mL) of oxalic acid(29 mg) in ethanol. The mixture was stirred at room temperature for 10min, and concentrated under reduced pressure. The residue wasrecrystallized from ethanol to give the title compound as white crystals(yield 59.6 mg, 44%).

¹H-NMR (DMSO-d₆) δ: 2.46 (3H, s), 2.48 (3H, s), 3.84 (3H, s), 3.90 (2H,s), 6.26 (1H, s), 7.25 (1H, s), 7.45-7.48 (2H, m), 7.53-7.60 (3H, m),7.68-7.72 (1H, m), 3H not detected.

Example 186N-Methyl-1-[4-methyl-1-(phenylsulfonyl)-5-(3-thienyl)-1H-pyrrol-3-yl]methanaminehydrochloride

To a solution (10 mL) of4-methyl-1-(phenylsulfonyl)-5-(3-thienyl)-1H-pyrrole-3-carbaldehyde (549mg) in tetrahydrofuran was added a 2 mol/L solution (1.7 mL) ofmethylamine in tetrahydrofuran, and the mixture was stirred at roomtemperature for 4 hr. The reaction mixture was added to a solution (10mL) of sodium borohydride (126 mg) in methanol, and the mixture wasstirred at room temperature for 30 min. Water was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated aqueous sodium hydrogencarbonate solution,water and saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by basicsilica gel column chromatography (eluent: ethylacetate-methanol=1:0→4:1) to give a free base of the title compound. Toa solution (10 mL) of the obtained free base in ethyl acetate was addeda 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL), and themixture was stood at room temperature for 30 min. The precipitatedproduct was collected by filtration, and recrystallized from ethanol togive the title compound as a colorless solid (yield 400 mg, 63%).

¹H-NMR (DMSO-d₆) δ: 1.81 (3H, s), 2.56 (3H, s), 3.96 (2H, s), 6.83-6.85(1H, m), 7.19-7.21 (1H, m), 7.38-7.41 (2H, m), 7.50-7.60 (3H, m),7.67-7.74 (2H, m), 9.01 (2H, br).

Example 1871-[5-Phenyl-1-({4-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

Under an argon atmosphere, 5-phenyl-1H-pyrrole-3-carbaldehyde (171 mg)was dissolved in tetrahydrofuran (10 mL), sodium hydride (60% in oil, 60mg) was added, and the mixture was stirred at room temperature for 15min. 15-Crown-5 (0.30 mL) was added and the mixture was further stirredat the same temperature for 15 min.4-[(Trifluoromethyl)sulfonyl]benzenesulfonyl chloride (432 mg) was addedand the reaction mixture was stirred at room temperature for 30 min.Water was added, and the mixture was extracted with ethyl acetate. Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluent: hexane-ethylacetate=9:1→4:1) to give5-phenyl-1-({4-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-1H-pyrrole-3-carbaldehyde(191 mg) as an orange solid. The obtained5-phenyl-1-({4-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-1H-pyrrole-3-carbaldehyde(191 mg) was subjected to a similar operation as in the synthesis ofExample 179 to give the title compound as a solid (yield 86 mg, 40%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 4.00 (2H, s), 6.49 (1H, s), 7.08-7.10(2H, m), 7.31-7.44 (3H, m), 7.75-7.81 (3H, m), 8.26-8.29 (2H, m), 8.89(2H, br).

Example 1881-[5-Phenyl-1-({3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

Using 3-[(trifluoromethyl)sulfonyl]benzenesulfonyl chloride, a procedureas in Example 187 was performed to give the title compound as a solid(yield 90 mg, 28%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 3.98 (2H, s), 6.50 (1H, s), 7.11-7.14(2H, m), 7.33-7.45 (3H, m), 7.75 (1H, s), 7.82 (1H, s), 8.01-8.05 (1H,m), 8.12-8.15 (1H, m), 8.15-8.52 (1H, m), 8.91 (2H, br).

Example 1891-[5-(2-Fluorophenyl)-1-({3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

Using 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (189 mg) and3-[(trifluoromethyl)sulfonyl]benzenesulfonyl chloride (432 mg), aprocedure as in Example 187 was performed to give the title compound asa solid (yield 78 mg, 15%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 4.00 (2H, s), 6.58 (1H, s), 7.10-7.25(3H, m), 7.51-7.60 (1H, m), 7.85 (1H, s), 7.90 (1H, s), 8.06-8.11 (1H,m), 8.22-8.25 (1H, m), 8.54-8.56 (1H, m), 8.91 (2H, br).

Example 190N-Methyl-1-[4-methyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanaminehydrochloride

A solution (20 mL) of methyl4-methyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (920 mg)in tetrahydrofuran was cooled to −78° C., a 1.5 mol/L toluene solution(6.3 mL) of diisobutylaluminum hydride was added dropwise, and themixture was further stirred at −78° C. for 30 min. 1 mol/L Hydrochloricacid (25 mL) was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. A solution (20 mL) of the residue in acetonitrile wascooled to 0° C., tetra-n-propylammonium perruthenate (110 mg),N-methylmorpholine N-oxide (554 mg) and molecular sieves 4A powder (2.0g) were added, and the mixture was stirred at room temperature for 2 hr.The reaction mixture was concentrated under reduced pressure, theresidue was suspended in ethyl acetate, and the mixture was filteredthrough celite. The filtrate was concentrated under reduced pressure,and the residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=9:1→2:1) to give4-methyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde as abrown oil (yield 461 mg, 55%).4-Methyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (460 mg)was dissolved in methanol (25 mL), and methylammonium chloride (952 mg)and sodium cyanoborohydride (266 mg) were added. The mixture was stirredat room temperature for 1 hr, and concentrated under reduced pressure.The residue was dissolved in water, and the solution was alkalized witha saturated aqueous sodium hydrogencarbonate solution and extracted withethyl acetate. The extract was washed with saturated brine, and driedover anhydrous sodium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by basic silica gel columnchromatography (eluent: hexane-ethyl acetate=9:1→ethyl acetate). Theobtained oil was dissolved in ethyl acetate (5 mL), and a 4 mol/Lhydrogen chloride-ethyl acetate solution (0.5 mL) was added. Theprecipitated crystal was collected by filtration, and vacuum-dried togive the title compound as a colorless solid (yield 196 mg, 37%).

¹H-NMR (DMSO-d₆) δ: 1.78 (3H, s), 2.58 (3H, s), 3.99 (2H, s), 6.95-7.10(2H, m), 7.20 (1H, m), 7.30-7.65 (6H, m), 7.70-7.90 (2H, m), 8.91 (2H,br).

Example 1911-{1-[(3-Chlorophenyl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanaminehydrochloride

A solution (15 mL) of methyl1-[(3-chlorophenyl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carboxylate(700 mg) in tetrahydrofuran was cooled to −78° C., a 1.5 mol/L toluenesolution (4.3 mL) of diisobutylaluminum hydride was added dropwise, andthe mixture was further stirred at −78° C. for 30 min. 1 mol/LHydrochloric acid (20 mL) was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. A solution (20 mL) of the residue inacetonitrile was cooled to 0° C., tetra-n-propylammonium perruthenate(76 mg), N-methylmorpholine N-oxide (377 mg) and molecular sieves 4Apowder (1.5 g) were added, and the mixture was stirred at roomtemperature for 2 hr. The reaction mixture was concentrated underreduced pressure, the residue was suspended in ethyl acetate, and thesuspension was filtered through celite. The filtrate was concentratedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (eluent: hexane-ethyl acetate=9:1→2:1) to give1-[(3-chlorophenyl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehydeas a brown solid (yield 565 mg, 88%).1-[(3-Chlorophenyl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde(560 mg) was dissolved in methanol (25 mL), and methylammonium chloride(1.05 g) and sodium cyanoborohydride (294 mg) were added. The mixturewas stirred at room temperature for 1 hr, and concentrated under reducedpressure. The residue was dissolved in water, and the solution wasalkalized with a saturated aqueous sodium hydrogencarbonate solution andextracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by basicsilica gel column chromatography (eluent: hexane-ethyl acetate=9:1→ethylacetate). The obtained oil was dissolved in ethyl acetate (5 mL), and a4 mol/L hydrogen chloride-ethyl acetate solution (0.5 mL) was added. Theprecipitated crystals were collected by filtration and vacuum-dried togive the title compound as a colorless solid (yield 154 mg, 24%).

¹H-NMR (DMSO-d₆) δ: 1.77 (3H, s), 2.56 (3H, s), 3.98 (2H, s), 6.95-7.05(2H, m), 7.30-7.60 (6H, m), 7.65-7.80 (2H, m), 8.99 (2H, br).

Example 1925-({4-[(Methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)pyrimidine-2-amine

To a solution (4 mL) of1-(2-chloropyrimidin-5-ylsulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde(139 mg) in tetrahydrofuran was added a 0.5 mol/L oxane solution (4 mL)of ammonia was added. The mixture was stirred at room temperature for 1hr, saturated aqueous sodium hydrogencarbonate solution was added, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was dissolved intetrahydrofuran solution (5 mL), a 2 mol/L tetrahydrofuran solution(0.75 mL) of methylamine was added, and the mixture was stirredovernight at room temperature. The reaction mixture was added to asolution (2 mL) of sodium borohydride (38 mg) in methanol, and themixture was stirred at room temperature for 5 min. To the reactionmixture was added saturated aqueous sodium hydrogencarbonate solution,and the mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by HPLC(ODS, 0.1% trifluoroacetic acid-containing water-0.1% trifluoroaceticacid-containing acetonitrile=9:1→0.1% trifluoroacetic acid-containingacetonitrile) to give trifluoroacetate of the title compound. Theobtained trifluoroacetate was neutralized with saturated aqueous sodiumhydrogencarbonate solution, and the mixture was extracted with ethylacetate. The extract was washed successively with saturated aqueoussodium hydrogencarbonate solution, water and saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the crystals were washed with diisopropyl ether togive the title compound as a colorless solid (yield 23 mg, 17%).

¹H-NMR (DMSO-d₆) δ: 2.27 (3H, s), 3.52 (2H, s), 6.31 (1H, s), 7.26-7.40(6H, m), 7.94 (2H, br), 8.00 (2H, s), 1H not detected.

Example 1931-[(Imidazo[1,2-a]pyrimidin-6-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]-N-methylmethanaminedihydrochloride

Under a nitrogen atmosphere, a solution of ethyl1-(imidazo[1,2-a]pyrimidin-6-ylsulfonyl)-5-phenyl-1H-pyrrole-3-carboxylate(242 mg) in tetrahydrofuran (10 mL) was cooled to C, a 1.5 mol/L toluenesolution (2.0 mL) of diisobutylaluminum was added with stirring. Themixture was stirred at the same temperature for 1 hr, and thetemperature was raised to −20° C. over 1 hr. Water (30 mL) was added,the mixture was stirred at the same temperature for 5 min, and thetemperature was raised to 0° C. over 10 min. Ethyl acetate (20 mL) wasadded, and the mixture was stirred at the same temperature for 15 min,and then at room temperature for 20 min. The gelated reaction productwas filtered through celite, and the celite was washed with ethylacetate. The organic layer was separated from the filtrate, washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was dissolved intetrahydrofuran (50 mL), manganese dioxide (75% chemically-treatedproduct, 2.0 g) was added, and the mixture was stirred at roomtemperature was for 2 hr. The reaction mixture was filtered throughcelite, and the celite was washed with ethyl acetate. The filtrate wasconcentrated under reduced pressure, and the residue was dissolved inabsolute tetrahydrofuran (5 mL). A 2 mol/L tetrahydrofuran solution (0.6mL) of methylamine was added, and the mixture was stirred at roomtemperature for 2 hr. The reaction mixture was added to a solution ofsodium borohydride (45 mg) in methanol (2 mL), and the mixture wasstirred at the same temperature for 20 min. The reaction mixture wasdiluted with ethyl acetate, washed with saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was dissolved in tetrahydrofuran (10 mL),di-tert-butyl bicarbonate (0.22 g), sodium hydrogencarbonate (84 mg) andwater (5 mL) were added, and the mixture was stirred at room temperaturefor 30 min. The reaction mixture was diluted with ethyl acetate, washedwith saturated brine, and dried over anhydrous magnesium sulfate, andthe solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), manganese dioxide (75%chemically-treated product, 1.0 g) was added, and the mixture wasstirred at room temperature for 2 days. The reaction mixture wasfiltered through celite, and the celite was washed with ethyl acetate.The filtrate was concentrated under reduced pressure, and the residuewas purified by silica gel column chromatography (eluent: hexane-ethylacetate=19:1→0:1) to give N-Boc compound of the title compound. Theobtained N-Boc compound was dissolved in ethanol (1 mL), and a 4 mol/Lhydrogen chloride-ethyl acetate solution (1 mL) was added. The mixturewas stirred at room temperature for 2 hr, and the solvent was evaporatedunder reduced pressure. The residue was triturated with ethylacetate-ethanol to give the title compound as a brown solid (yield 8.5mg, 3%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 4.02-4.05 (2H, m), 6.49 (1H, s),7.16-7.19 (2H, m), 7.32-7.44 (3H, m), 7.79 (1H, s), 7.92-7.99 (2H, m),8.29-8.30 (1H, m), 8.97 (2H, br), 9.23-9.24 (1H, m), 1H not detected.

Example 194N-Methyl-1-[1-(pyridazin-3-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]methanaminefumarate

Under a nitrogen atmosphere, a solution of ethyl1-(pyridazin-3-ylsulfonyl)-5-phenyl-1H-pyrrole-3-carboxylate (567 mg) intetrahydrofuran (16 mL) was cooled to −78° C., and a 1.5 mol/L toluenesolution (6.4 mL) of diisobutylaluminum was added with stirring. Thetemperature of the reaction mixture was raised to −20° C. over 1 hr.Water (75 mL) was added, the mixture was stirred at the same temperaturefor 5 min, and the temperature was raised to 0° C. over 10 min. Ethylacetate (75 mL) was added, and the mixture was stirred at the sametemperature for 15 min, and then at room temperature for 20 min. Thereaction mixture was filtered through celite, and the celite was washedwith ethyl acetate. The organic layer was separated from the filtrate,washed with saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was dissolved intetrahydrofuran (30 mL), manganese dioxide (75% chemically-treatedproduct, 5.0 g) was added, and the mixture was stirred at roomtemperature for 1 hr. The reaction mixture was filtered through celite,and the celite was washed with ethyl acetate. The filtrate wasconcentrated under reduced pressure, and the residue was dissolved inabsolute tetrahydrofuran (15 mL). A 2 mol/L tetrahydrofuran solution(1.5 mL) of methylamine was added, and the mixture was stirred at roomtemperature overnight. The reaction mixture was added to a solution ofsodium borohydride (66 mg) in methanol (5 mL), and the mixture wasstirred at the same temperature for 20 min. To the reaction mixture wasadded saturated aqueous sodium hydrogencarbonate solution, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby HPLC (ODS, 0.1% trifluoroacetic acid-containing water-0.1%trifluoroacetic acid-containing acetonitrile=9:1→0.1% trifluoroaceticacid-containing acetonitrile) to give trifluoroacetate of the titlecompound. The obtained trifluoroacetate was neutralized with saturatedaqueous sodium hydrogencarbonate solution, and the mixture was extractedwith ethyl acetate. The extract was washed successively with saturatedaqueous sodium hydrogencarbonate solution, water and saturated brine,and dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure to give a free base (59 mg) of thetitle compound. The obtained free base (59 mg) was dissolved in methanol(2 mL) and ethyl acetate (2 mL), and fumaric acid (21 mg) was added. Thesolvent was evaporated under reduced pressure, and the residue wasrecrystallized from ethyl acetate-methanol to give the title compound asa pale-yellow solid (yield 41 mg, 6%).

¹H-NMR (DMSO-d₆) δ: 2.42 (3H, s), 3.82 (2H, s), 6.41 (1H, s), 6.47 (2H,s), 7.09-7.12 (2H, m), 7.29-7.38 (3H, m), 7.63 (1H, s), 7.80-7.83 (1H,m), 7.91-7.96 (1H, m), 9.48-9.50 (1H, m), 3H not detected.

Example 195N,N-Dimethyl-1-[5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanaminehydrochloride

To a solution (10 mL) of 5-phenyl-1H-pyrrole-3-carbaldehyde (140 mg) intetrahydrofuran was added sodium hydride (60% in oil, 66 mg) at roomtemperature, and the mixture was stirred for 30 min. 15-Crown-5 (361 mg)was added dropwise, and the mixture was stirred for 30 min.Benzenesulfonyl chloride (217 mg) was added, and the mixture was furtherstirred for 1 hr. To the reaction mixture was added saturated brine, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=9:1→4:1) to give5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde as a colorlessoil. The obtained oil was dissolved in methanol (20 mL), a 2 mol/Ltetrahydrofuran solution (4.1 mL) of dimethylamine was added at roomtemperature, and the mixture was stirred for 30 min. Sodium borohydride(93 mg) was added at room temperature, and the mixture was stirred for10 min. 1 mol/L Hydrochloric acid (30 mL) was added, and the mixture wasstirred for 5 min. The reaction mixture was alkalized with a saturatedaqueous sodium hydrogencarbonate solution and extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent: ethylacetate-methanol=4:1), and dissolved in ethyl acetate (5 mL). A 4 mol/Lhydrogen chloride-ethyl acetate solution (1 mL) was added, and themixture was concentrated under reduced pressure. The residue wascrystallized from ethyl acetate to give the title compound as colorlesscrystals (yield 200 mg, 65%).

¹H-NMR (DMSO-d₆) δ: 2.67 (6H, s), 4.12 (2H, s), 6.48 (1H, br), 7.13-7.17(2H, m), 7.32-7.43 (5H, m), 7.48-7.54 (2H, m), 7.58-7.73 (1H, m), 7.80(1H, br).

Example 196N,N-Dimethyl-1-[5-phenyl-1-(3-thienylsulfonyl)-1H-pyrrol-3-yl]methanaminehydrochloride

To a solution (10 mL) of 5-phenyl-1H-pyrrole-3-carbaldehyde (100 mg) intetrahydrofuran was added sodium hydride (60% in oil, 47 mg) at roomtemperature, and the mixture was stirred for 30 min. 15-Crown-5 (257 mg)was added dropwise, and the mixture was stirred for 30 min.(3-Thienyl)sulfonyl chloride (160 mg) was added, and the mixture wasfurther stirred for 1 hr. Saturated brine was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (eluent: hexane-ethyl acetate=4:1→3:2)to give 5-phenyl-1-(3-thienylsulfonyl)-1H-pyrrole-3-carbaldehyde as acolorless oil. The obtained oil was dissolved in methanol (10 mL), a 2mol/L tetrahydrofuran solution (2.1 mL) of dimethylamine was added atroom temperature, and the mixture was stirred for 30 min. Sodiumborohydride (47 mg) was added at room temperature, and the mixture wasstirred for 10 min. 1 mol/L Hydrochloric acid (30 mL) was added, and themixture was stirred for 5 min. The reaction mixture was alkalized with asaturated aqueous sodium hydrogencarbonate solution and extracted withethyl acetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent: ethylacetate-methanol=4:1), and dissolved in ethyl acetate (5 mL). A 4 mol/Lhydrogen chloride-ethyl acetate solution (1 mL) was added, and themixture was concentrated under reduced pressure. The residue wascrystallized from ethyl acetate to give the title compound as colorlesscrystals (yield 70 mg, 45%).

¹H-NMR (DMSO-d₆) δ: 2.67 (6H, s), 4.12 (2H, s), 6.53 (1H, d, J=1.8 Hz),7.00-7.02 (1H, m), 7.18-7.21 (2H, m), 7.33-7.44 (3H, m), 7.72-7.74 (1H,m), 7.76 (1H, d, J=1.8 Hz), 7.99-8.00 (1H, m), 10.84 (1H, br).

Example 197N,N-Dimethyl-1-{5-phenyl-1-(3-pyridinesulfonyl)-1H-pyrrol-3-yl}methanaminedihydrochloride

5-Phenyl-1-(3-pyridinesulfonyl)-1H-pyrrole-3-carbaldehyde (230 mg) wasdissolved in dichloromethane (20 mL), triethylamine (0.52 mL),dimethylamine hydrochloride (302 mg), sodium triacetoxyborohydride (1.06g) were added, and the mixture was stirred at room temperature for 2 hr.The reaction mixture was diluted with ethyl acetate, washed successivelywith saturated aqueous sodium hydrogencarbonate solution, water andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (eluent: ethylacetate-methanol=1:0→1:1) to give a free base of the title compound. Theobtained free base was dissolved in ethyl acetate (3 mL), a 4 mol/Lhydrogen chloride-ethyl acetate solution (1 ml) and ethanol (2 mL) wereadded, and the mixture was concentrated under reduced pressure. Theresidue was crystallized from ethanol to give the title compound (yield138 mg, 45%).

¹H-NMR (DMSO-d₆) δ: 2.67-2.69 (6H, m), 4.12-4.14 (2H, m), 6.54 (1H, s),7.16-7.18 (2H, m), 7.35-7.45 (3H, m), 7.54-7.59 (1H, m), 7.64-7.84 (2H,m), 8.48 (1H, s), 8.84-8.86 (1H, m), 10.50 (1H, br).

Example 1981-[4-Ethyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

Using tert-butyl{[4-ethyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(589 mg), a procedure as in Example 33 was performed to give the titlecompound as a pale-yellow solid (yield 149 mg, 30%).

¹H-NMR (CDCl₃) δ: 0.87 (3H, t, J=7.5 Hz), 2.25 (2H, q, J=7.5 Hz), 2.71(3H, brs), 4.09 (2H, brs), 6.97-7.00 (2H, m), 7.25-7.45 (7H, m),7.49-7.54 (1H, m), 7.93 (1H, s), 9.92 (2H, brs).

Example 1991-[4-Isopropyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

Using tert-butyl{[4-isopropyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(218 mg), a procedure as in Example 33 was performed to give the titlecompound as colorless crystals (yield 57 mg, 30%).

¹H-NMR (CDCl₃) δ: 0.96 (6H, d, J=7.2 Hz), 2.60-2.70 (1H, m), 2.83 (3H,s), 4.18 (2H, s), 6.92-6.96 (2H, m), 7.23-7.28 (2H, m), 7.32-7.40 (3H,m), 7.45-7.54 (3H, m), 8.02 (1H, s), 10.2 (1H, br), 1H not detected.

Example 2002-({4-[(Methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzoicacid hydrochloride

2-[(4-{[(tert-Butoxycarbonyl)(methyl)amino]methyl}-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoicacid (256 mg) was dissolved in ethyl acetate (1 mL), and 4 mol/Lhydrogen chloride-ethyl acetate solution (1 mL) was added at roomtemperature. After stirring at the same temperature for 3 hr, thereaction mixture was homogenized with methanol, activated carbon wasadded and the mixture was filtered through celite. The filtrate wasconcentrated under reduced pressure, and the residue was crystallizedfrom ethyl acetate. The obtained crystal was recrystallized from a mixedsolvent of ethyl acetate and ethanol to give the title compound ascolorless crystals (yield 110 mg, 50%).

¹H-NMR (DMSO-d₆) δ: 2.49-2.55 (3H, m), 4.01 (2H, br), 6.50 (1H, d, J=1.8Hz), 6.99 (1H, d, J=7.2 Hz), 7.07-7.10 (2H, m), 7.24-7.29 (2H, m),7.33-7.38 (1H, m), 7.46-7.51 (1H, m), 7.62 (1H, d, J=1.8 Hz), 7.66-7.77(2H, m), 9.15 (2H, br).

Example 2013-({4-[(Methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzoicacid hydrochloride

Using3-[(4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoicacid (105 mg), a procedure as in Example 200 was performed to give thetitle compound as colorless crystals (yield 58 mg, 58%).

¹H-NMR (DMSO-d₆) δ: 2.50-2.51 (3H, m), 3.99 (2H, brs), 6.45 (1H, d,J=1.5 Hz), 7.11-7.13 (2H, m), 7.32-7.42 (3H, m), 7.64-7.66 (2H, m), 7.76(1H, d, J=1.5 Hz), 7.81 (1H, s), 8.19-8.22 (1H, m), 8.95 (2H, br), 1Hnot detected.

Example 2023-({4-[(Methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzamidehydrochloride

Using tert-butyl[(1-{[3-(aminocarbonyl)phenyl]sulfonyl}-5-phenyl-1H-pyrrol-3-yl)methyl]methylcarbamate(193 mg), a procedure as in Example 33 was performed to give the titlecompound as colorless crystals (yield 95 mg, 57%).

¹H-NMR (DMSO-d₆) δ: 2.49-2.51 (3H, m), 3.98 (2H, s), 6.45 (1H, d, J=1.8Hz), 7.12 (2H, d, J=6.9 Hz), 7.32-7.47 (4H, m), 7.57-7.64 (2H, m), 7.77(1H, d, J=1.2 Hz), 7.94 (1H, s), 8.14-8.21 (2H, m), 9.00 (2H, br).

Example 203N-Cyclopropyl-3-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzamidehydrochloride

Using tert-butyl{[1-({3-[(cyclopropylamino)carbonyl]phenyl}sulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}methylcarbamate(162 mg), a procedure as in Example 33 was performed to give the titlecompound as colorless crystals (yield 42 mg, 30%).

¹H-NMR (DMSO-d₆) δ: 0.57-0.74 (4H, m), 2.48 (3H, brs), 2.80-2.88 (1H,m), 3.97 (2H, brs), 6.46 (1H, d, J=1.8 Hz), 7.11-7.13 (2H, m), 7.32-7.48(4H, m), 7.59 (1H, t, J=7.8 Hz), 7.77 (1H, s), 7.86 (1H, s), 8.11 (1H,d, J=7.8 Hz), 8.74 (1H, d, J=3.9 Hz), 9.12 (2H, br).

Example 204N-Methyl-3-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzamidehydrochloride

Using tert-butylmethyl{[1-({3-[(methylamino)carbonyl]phenyl}sulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}carbamate(157 mg), a procedure as in Example 33 was performed to give the titlecompound as colorless crystals (yield 59 mg, 43%).

¹H-NMR (DMSO-d₆) δ: 2.48-2.52 (3H, m), 2.78 (3H, d, J=4.5 Hz), 3.97 (2H,brs), 6.46 (1H, d, J=1.8 Hz), 7.10-7.13 (2H, m), 7.31-7.47 (4H, m), 7.60(1H, t, J=7.8 Hz), 7.77 (1H, d, J=1.8 Hz), 7.91-7.92 (1H, m), 8.13 (1H,d, J=7.8 Hz), 8.75 (1H, q, J=4.5 Hz), 9.07 (2H, br).

Example 205N,N-Dimethyl-3-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzamidehydrochloride

Using tert-butyl{[1-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}methylcarbamate(168 mg), a procedure as in Example 33 was performed to give the titlecompound as colorless crystals (yield 80 mg, 55%).

¹H-NMR (DMSO-d₆) δ: 2.49-2.51 (3H, m), 2.77 (3H, brs), 2.97 (3H, brs),3.97 (2H, brs), 6.47 (1H, d, J=1.5 Hz), 7.13-7.16 (2H, m), 7.32-7.47(5H, m), 7.55-7.60 (1H, m), 7.73-7.76 (2H, m), 9.02 (2H, br).

Example 206N-Methyl-1-(1-{[3-(morpholin-4-ylcarbonyl)phenyl]sulfonyl}-5-phenyl-1H-pyrrol-3-yl)methanaminehydrochloride

Using tert-butylmethyl[(1-{[3-(morpholin-4-ylcarbonyl)phenyl]sulfonyl}-5-phenyl-1H-pyrrol-3-yl)methyl]carbamate(164 mg), a procedure as in Example 33 was performed to give the titlecompound as colorless crystals (yield 95 mg, 66%).

¹H-NMR (CDCl₃) δ: 2.54 (3H, s), 3.26 (2H, br), 3.50-3.80 (6H, m), 3.96(2H, s), 6.48 (1H, d, J=2.1 Hz), 7.15-7.18 (2H, m), 7.24-7.40 (5H, m),7.48-7.49 (1H, m), 7.57-7.60 (1H, m), 7.69 (1H, d, J=2.1 Hz), 2H notdetected.

Example 2072-[3-({4-[(Methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)phenyl]propan-2-ol

To a solution of tert-butyl[1-(5-phenyl-1-{[3-(1-methyl-1-hydroxyethyl)phenyl]sulfonyl}-1H-pyrrol-3-yl)methyl]carbamate(334 mg) in ethanol (4 mL) was added 4 mol/L hydrogen chloride-ethylacetate solution (4.0 mL) and the mixture was stirred at roomtemperature for 3 hr. After the reaction mixture was concentrated underreduced pressure, saturated aqueous sodium hydrogencarbonate solutionwas added to the residue, and the mixture was extracted with ethylacetate. The extract was washed with saturated aqueous sodiumhydrogencarbonate solution, water and saturated brine, dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by basic silica gel columnchromatography (eluent: ethyl acetate) to give the title compound as awhite solid (yield 203 mg, 76%).

¹H-NMR (CDCl₃) δ: 1.44 (6H, s), 2.44 (3H, s), 3.59 (2H, s), 6.14 (1H, d,J=2.1 Hz), 7.23-7.37 (8H, m), 7.44-7.46 (1H, m), 7.59-7.62 (1H, m), 2Hnot detected.

Example 2082-Fluoro-4-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)benzonitrilehydrochloride

Using tert-butyl({1-[(4-cyano-3-fluorophenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)carbamate(54.7 mg) and 4 mol/L hydrogen chloride-ethyl acetate solution (4 mL), aprocedure as in Example 30 was performed to give the title compound as awhite solid (yield 6.9 mg, 14%).

¹H-NMR (CDCl₃) δ: 2.65 (3H, brs), 4.01 (2H, brs), 6.49 (1H, d, J=1.8Hz), 7.15-7.17 (3H, m), 7.31-7.35 (3H, m), 7.40-7.43 (1H, m), 7.60-7.65(1H, m), 7.73 (1H, d, J=1.8 Hz), 9.93 (2H, brs).

Example 209N-Methyl-1-(5-phenyl-1-{[3-(1H-tetrazol-5-yl)phenyl]sulfonyl}-1H-pyrrol-3-yl)methanaminehydrochloride

To a solution (10 mL) of tert-butylmethyl[(5-phenyl-1-{[3-(1H-tetrazol-5-yl)phenyl]sulfonyl}-1H-pyrrol-3-yl)methyl]carbamate(52 mg) in methanol was added 4 mol/L hydrogen chloride-ethyl acetatesolution (2 ml), and the mixture was stirred at 65° C. for 1.5 hr andconcentrated under reduced pressure. The residue was crystallized fromethyl acetate to give the title compound as crystals (yield 42 mg, 86%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 4.00 (2H, t, J=5.6 Hz), 6.45 (1H, s),7.12 (1H, d, J=1.7 Hz), 7.14 (1H, s), 7.27-7.37 (3H, m), 7.55 (1H, dd,J=1.1, 10.0 Hz), 7.72-7.81 (2H, m), 8.08 (1H, t, J=1.7 Hz), 8.37 (1H, d,J=8.3 Hz), 8.98 (2H, brs).

Example 2102-({4-[(Methylamino)methyl]-2-(pyridin-3-yl)-1H-pyrrol-1-yl}sulfonyl)benzonitrile0.5 oxalic acid salt

Using tert-butyl{[(2-cyanophenyl)sulfonyl-5-(3-pyridyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(178 mg), a procedure as in Example 30 was performed to give a free baseof the title compound as a yellow oil. To a solution (4 mL) of theobtained free base in ethanol was added a solution (2 mL) of oxalic acid(10 mg) in ethanol, and reaction mixture was stirred at room temperaturefor 30 min. The reaction mixture was concentrated under reducedpressure, and the residue was recrystallized from methanol to give thetitle compound as a white solid (yield 49 mg, 32%).

¹H-NMR (DMSO-d₆) δ: 2.40 (3H, s), 3.77 (2H, s), 6.52 (1H, d, J=2.1 Hz),7.32-7.39 (2H, m), 7.57-7.61 (1H, m), 7.67 (1H, s), 7.73-7.79 (1H, m),7.86-7.92 (1H, m), 8.10-8.13 (1H, m), 8.23 (1H, d, J=2.1 Hz), 8.55-8.57(1H, m), 2H not detected.

Example 211N-Methyl-1-(1-{[3-(methylsulfonyl)phenyl]sulfonyl}-5-(3-thienyl)-1H-pyrrol-3-yl)methanaminehydrochloride

Using tert-butylmethyl[(1-{[3-(methylsulfonyl)phenyl]sulfonyl}-5-(3-thienyl)-1H-pyrrol-3-yl)methyl]carbamate(302 mg), a procedure as in Example 33 was performed to give the titlecompound as a white solid (yield 46 mg, 18%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 3.27 (3H, s), 3.98 (2H, s), 6.98-7.00(1H, m), 7.37-7.38 (1H, m), 7.56-7.59 (1H, m), 7.77-7.87 (4H, m),8.25-8.28 (1H, m), 9.00 (2H, brs).

Example 212N-Methyl-1-(1-{[3-(methylsulfonyl)phenyl]sulfonyl}-5-(pyridin-3-yl)-1H-pyrrol-3-yl)methanaminedihydrochloride

Using tert-butylmethyl[(1-{[3-(methylsulfonyl)phenyl]sulfonyl}-5-(pyridin-3-yl)-1H-pyrrol-3-yl)methyl]carbamate(300 mg), a procedure as in Example 30 was performed to give the titlecompound as a white solid (yield 85 mg, 42%).

¹H-NMR (DMSO-d₆) δ: 2.46 (3H, t, J=5.4 Hz), 3.30 (3H, s), 3.99 (2H, t,J=5.4 Hz), 5.67 (1H, brs), 6.73 (1H, d, J=1.5 Hz), 7.66-7.70 (1H, m),7.78 (1H, brs), 7.86-7.95 (4H, m), 8.28-8.32 (1H, m), 8.52 (1H, brs),8.75-8.76 (1H, m), 9.31 (2H, brs).

Example 2131-[1-(2-Chloropyridin-3-ylsulfonyl)-5-phenyl-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

To a solution (3 mL) of tert-butyl{[1-(2-chloro-3-pyridinesulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}methylcarbamate(70 mg) in ethyl acetate was added 4 mol/L hydrogen chloride-ethylacetate solution (1 mL), and the mixture was stirred at room temperaturefor 3 hr. The solvent was evaporated under reduced pressure, and theresidue was crystallized from ethanol-ethyl acetate to give the titlecompound (yield 29 mg, 49%).

¹H-NMR (DMSO-d₆) δ: 2.56 (3H, s), 4.04 (2H, s), 6.48 (1H, s), 6.99-7.02(2H, m), 7.25-7.36 (4H, m), 7.66-7.69 (1H, m), 7.83 (1H, s), 8.60-8.62(1H, m), 8.79 (2H, br).

Example 214N-Methyl-1-[1-(5-methyl-3-pyridinesulfonyl)-5-phenyl-1H-pyrrol-3-yl]methanaminefumarate

To a solution (5 mL) of tert-butyl{[1-(6-chloro-5-methyl-3-pyridinesulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}methylcarbamate(237 mg) in tetrahydrofuran was added hydrazine (160 mg) with stirringat room temperature. After stirring at the same temperature for 3 hr,saturated aqueous sodium hydrogencarbonate solution was added and themixture was extracted with ethyl acetate. The extract was washed withwater and saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was dissolved intetrahydrofuran (30 mL), manganese dioxide (75% chemically-treatedproduct, 1.0 g) was added, the mixture was stirred at room temperaturefor 10 min. The reaction product was filtered through celite, and thecelite was washed with ethyl acetate. The filtrate was concentratedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (eluent: hexane-ethyl acetate=19:1→1:1) to giveN-Boc-compound (129 mg) of the title compound. The obtained N-Boccompound was dissolved in ethanol (2 mL), and a 4 mol/L hydrogenchloride-ethyl acetate solution (1 mL) was added. After stirring at roomtemperature for 2 hr, the solvent was evaporated under reduced pressure,saturated aqueous sodium hydrogencarbonate solution was added, and themixture was extracted with ethyl acetate. The extract was washed withwater and saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue (93 mg) was dissolvedin methanol (3 mL), and fumaric acid (29 mg) was added. The mixture wasstood at room temperature for 30 min, and the precipitated crystals werecollected by filtration and washed with methanol to give the titlecompound as a colorless solid (yield 91 mg, 40%).

¹H-NMR (DMSO-d₆) δ: 2.27 (3H, s), 2.38 (3H, s), 3.75 (2H, s), 6.37 (1H,s), 6.47 (2H, s), 7.15-7.17 (2H, m), 7.36-7.45 (4H, m), 7.58 (1H, s),8.28 (1H, s), 8.68 (1H, s), 3H not detected.

Example 2155-({4-[(Methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)pyridin-2-olhydrochloride

tert-Butyl{[1-(6-chloro-3-pyridinesulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}methylcarbamate(175 mg) was dissolved in tetrahydrofuran (10 mL), 8 mol/L aqueoussodium hydroxide solution (3.8 mL) was added, and the mixture wasstirred at 50° C. for 2 days. Water was added to the reaction mixture,and the mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent: hexane-ethyl acetate=19:1→0:1) togive a free base of the title compound. To a solution (1 mL) of theobtained free base in ethanol was added a 4 mol/L hydrogenchloride-ethyl acetate solution (2 mL). After stirring at roomtemperature for 4 hr, the solvent was evaporated under reduced pressure,and the residue was crystallized from ethanol-ethyl acetate to give thetitle compound (yield 40 mg, 27%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 3.97-4.01 (2H, m), 6.32-6.36 (1H, m),6.47 (1H, s), 7.20-7.23 (4H, m), 7.37-7.48 (3H, m), 7.66 (1H, s), 8.94(2H, br), 12.35 (1H, br).

Example 2165-({4-[(Methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)pyridine-2-carbonitrilehydrochloride

Under an argon atmosphere, a mixture of tert-butyl{[1-(6-chloro-3-pyridinesulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}methylcarbamate(100 mg), zinc (II) cyanide (51 mg),tetrakis(triphenylphosphine)palladium (50 mg) and N,N-dimethylformamide(4 mL) was stirred at 100° C. for 2 hr. The reaction mixture was dilutedwith ethyl acetate, and washed successively saturated aqueous sodiumhydrogencarbonate solution, water and saturated brine. The mixture wasdried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=19:1→7:3) to give N-Boccompound of the title compound. The obtained N-Boc compound wasdissolved in ethyl acetate (2 mL), and a 4 mol/L hydrogen chloride-ethylacetate solution (2 mL) was added. The mixture was stirred at roomtemperature for 1 hr, and the solvent was evaporated under reducedpressure. The residue was crystallized from ethanol to give the titlecompound (yield 57 mg, 68%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, s), 3.98 (2H, s), 6.52 (1H, s), 7.15-7.17(2H, m), 7.37-7.47 (3H, m), 7.79 (1H, s), 8.04-8.07 (1H, m), 8.22-8.24(1H, m), 8.61-8.62 (1H, m), 9.03 (2H, br).

Example 217N-Methyl-1-{1-[(6-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methanaminedihydrochloride

tert-Butyl({[1-(6-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)methylcarbamate(113 mg, 0.26 mmol) was dissolved in ethanol (2 mL), 4 mol/L hydrogenchloride-ethyl acetate solution (1 mL) was added, and the mixture wasstirred at room temperature for 1 hr. The solvent was evaporated underreduced pressure, and the residue was recrystallized from ethanol togive the title compound (yield 40 mg, 38%).

¹H-NMR (DMSO-d₆) δ: 2.50-2.53 (6H, m), 3.97-3.99 (2H, m), 6.46 (1H, s),7.16-7.18 (2H, m), 7.38-7.44 (4H, m), 7.65-7.75 (2H, m), 8.34 (1H, s),8.98 (2H, br), 1H not detected.

Example 218N-Methyl-1-[1-(pyridin-3-ylsulfonyl)-5-(3-thienyl)-1H-pyrrol-3-yl]methanaminehydrochloride

Using tert-butyl{[1-(pyridin-3-ylsulfonyl)-5-(3-thienyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(182 mg), a procedure as in Example 217 was performed to give the titlecompound as colorless crystals (yield 64 mg, 41%).

¹H-NMR (CDCl₃) δ: 2.60 (3H, s), 3.98 (2H, brs), 6.57 (1H, brs), 7.00(1H, brd, J=4.5 Hz), 7.16 (1H, brs), 7.26-7.31 (2H, m), 7.70 (2H, brs),8.61 (1H, brs), 8.73 (1H, brs), 9.86 (2H, brs).

Example 2191-[5-(4-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminedihydrochloride

tert-Butyl{[5-(4-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(293 mg) was dissolved in dichloromethane (1 mL), trifluoroacetic acid(1 mL) was added at 0° C., and the mixture was stirred at roomtemperature for 3 hr. The reaction solution was basified by the dropwiseaddition to 6% aqueous sodium hydrogencarbonate solution, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by basicsilica gel column chromatography (eluent: hexane-ethyl acetate=1:1→1:9)to give a free base of the title compound as a pale-yellow oil. Theobtained free base was dissolved in ethyl acetate (5 mL). A 4 mol/Lhydrogen chloride-ethyl acetate solution (1 mL) was added, and themixture was concentrated under reduced pressure. The residue wasrecrystallized from ethyl acetate-ethanol to give the title compound ascolorless crystals (yield 110 mg, 40%).

¹H-NMR (DMSO-d₆) δ: 2.47-2.51 (3H, m), 3.97 (2H, t, J=6.0 Hz), 6.52-6.53(1H, m), 7.15-7.26 (4H, m), 7.57-7.61 (1H, m), 7.79-7.85 (2H, m), 8.00(1H, d, J=2.4 Hz), 8.85-8.87 (1H, m), 9.22 (2H, br), 1H not detected.

Example 220N-Methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanaminedihydrochloride

Using tert-butylmethyl{[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate(210 mg), a procedure as in Example 219 was performed to give the titlecompound as colorless crystals (yield 67 mg, 34%).

¹H-NMR (DMSO-d₆) δ: 1.80 (3H, s), 2.49-2.53 (3H, m), 4.00 (2H, t, J=5.4Hz), 6.46 (1H, d, J=2.4 Hz), 6.83 (1H, d, J=7.8 Hz), 7.13-7.22 (2H, m),7.33-7.39 (1H, m), 7.59-7.63 (1H, m), 7.80-7.85 (2H, m), 8.46 (1H, d,J=2.4 Hz), 8.88-8.90 (1H, m), 9.27 (2H, br), 1H not detected.

Example 2211-[5-(4-Fluoro-2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminedihydrochloride

Using tert-butyl{[5-(4-fluoro-2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(216 mg), a procedure as in Example 219 was performed to give the titlecompound as colorless crystals (yield 81 mg, 40%).

¹H-NMR (DMSO-d₆) δ: 1.80 (3H, s), 2.49-2.51 (3H, m), 4.00 (2H, t, J=6.0Hz), 6.47 (1H, d, J=2.1 Hz), 6.85-6.90 (1H, m), 6.98-7.12 (2H, m),7.61-7.65 (1H, m), 7.81-7.88 (2H, m), 8.51 (1H, d, J=2.7 Hz), 8.89-8.91(1H, m), 9.29 (2H, br), 1H not detected.

Example 222N-Methyl-1-[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanaminedihydrochloride

Using tert-butylmethyl{[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate(200 mg), a procedure as in Example 219 was performed to give the titlecompound as colorless crystals (yield 125 mg, 67%).

¹H-NMR (DMSO-d₆) δ: 1.71 (3H, s), 2.49-2.51 (3H, m), 3.98 (2H, t, J=5.7Hz), 6.49 (1H, d, J=2.1 Hz), 7.16-7.23 (2H, m), 7.58-7.62 (1H, m),7.79-7.86 (2H, m), 8.50-8.51 (1H, m), 8.87-8.89 (1H, m), 9.30 (2H, br),1H not detected.

Example 2233-[4-[(Methylamino)methyl]-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-2-yl]benzonitrilehydrochloride

Using tert-butyl{[5-(3-cyanophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(298 mg), a procedure as in Example 219 was performed to give the titlecompound as colorless crystals (yield 132 mg, 52%).

¹H-NMR (DMSO-d₆) δ: 2.48-2.51 (3H, m), 3.98 (2H, brs), 6.65 (1H, d,J=1.8 Hz), 7.51-7.65 (4H, m), 7.85-7.95 (3H, m), 8.55 (1H, d, J=2.4 Hz),8.88-8.90 (1H, m), 9.25 (2H, br).

Example 2241-[5-(2-Chlorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminedihydrochloride

Using tert-butyl{[5-(2-chlorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(171 mg), a procedure as in Example 219 was performed to give the titlecompound as colorless crystals (yield 74 mg, 46%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, br), 4.01 (2H, t, J=6.0 Hz), 5.40 (1H,br), 6.55 (1H, d, J=2.1 Hz), 7.13-7.16 (1H, m), 7.35-7.40 (1H, m),7.47-7.51 (2H, m), 7.61-7.65 (1H, m), 7.84-7.93 (2H, m), 8.57 (1H, d,J=2.1 Hz), 8.89-8.91 (1H, m), 9.23 (2H, br).

Example 2251-[5-(2,4-Difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminedihydrochloride

Using tert-butyl{[5-(2,4-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(110 mg), a procedure as in Example 219 was performed to give the titlecompound as colorless crystal (yield 58 mg, 56%).

¹H-NMR (DMSO-d₆) δ: 2.48-2.51 (3H, m), 3.98 (2H, t, J=5.7 Hz), 6.62 (1H,d, J=1.8 Hz), 7.13-7.17 (2H, m), 7.28-7.36 (1H, m), 7.62-7.66 (1H, m),7.86-7.95 (2H, m), 8.61 (1H, d, J=2.4 Hz), 8.89-8.91 (1H, m), 9.31 (2H,br), 1H not detected.

Example 2261-[5-(2,5-Difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

Using tert-butyl{[5-(2,5-difluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(105 mg), a procedure as in Example 219 was performed to give the titlecompound as colorless crystals (yield 39 mg, 43%).

¹H-NMR (DMSO-d₆) δ: 2.50-2.51 (3H, m), 3.99 (2H, brs), 6.62 (1H, d,J=1.8 Hz), 7.00-7.06 (1H, m), 7.27-7.44 (2H, m), 7.63-7.67 (1H, m), 7.86(1H, br), 7.94-7.97 (1H, m), 8.65 (1H, d, J=2.7 Hz), 8.90-8.92 (1H, m),9.08 (2H, m).

Example 2271-[5-(4-Chloro-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminedihydrochloride

Using tert-butyl{[5-(4-chloro-2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(103 mg), a procedure as in Example 219 was performed to give the titlecompound as colorless crystals (yield 32 mg, 33%).

¹H-NMR (DMSO-d₆) δ: 2.47-2.52 (3H, m), 3.97 (2H, t, J=6.0 Hz), 5.10 (1H,br), 6.64 (1H, brs), 7.15 (1H, t, J=7.8 Hz), 7.34-7.36 (1H, m),7.50-7.53 (1H, m), 7.62-7.67 (1H, m), 7.88 (1H, brs), 7.95-7.98 (1H, m),8.64 (1H, d, J=2.4 Hz), 8.90 (1H, d, J=4.8 Hz), 9.33 (2H, br).

Example 2281-[5-(3-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminehydrochloride

tert-Butyl{[5-(3-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(280 mg) was dissolved in ethyl acetate (3 mL), 4 mol/L hydrogenchloride-ethyl acetate solution (6 mL) was added, and the mixture wasstirred at room temperature for 16 hr. The reaction solution wasbasified by the dropwise addition to 6% aqueous sodium hydrogencarbonatesolution, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by basic silica gel column chromatography (eluent: ethylacetate-hexane=1:1→9:1) to give a free base of the title compound as apale-yellow oil. The obtained free base was dissolved in ethyl acetate.A 4 mol/L hydrogen chloride-ethyl acetate solution was added, and themixture was concentrated under reduced pressure. The residue wascrystallized from ethyl acetate and hexane, and recrystallized fromethyl acetate-ethanol to give the title compound as colorless crystals(yield 84 mg, 35%).

¹H-NMR (DMSO-d₆) δ: 2.49-2.51 (3H, m), 3.97 (2H, s), 6.57 (1H, d, J=1.8Hz), 6.98-7.02 (2H, m), 7.27-7.33 (1H, m), 7.40-7.47 (1H, m), 7.58-7.62(1H, m), 7.80-7.87 (2H, m), 8.54 (1H, d, J=2.7 Hz), 8.86-8.88 (1H, m),9.06 (2H, br).

Example 229N-Methyl-1-[1-(phenylsulfonyl)-5-(pyrimidin-5-yl)-1H-pyrrol-3-yl]methanaminehydrochloride

tert-Butyl{[5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (170mg), pyrimidin-5-ylboronic acid (123 mg), sodium carbonate (147 mg) andtetrakis(triphenylphosphine)palladium (46 mg) was added to1,2-dimethoxyethane (10 mL) and water (5 mL), and the mixture wasstirred at 90° C. for 3 hr. After the reaction mixture was cooled toroom temperature, water was added, and the mixture was extracted withethyl acetate. The extract was washed with water and saturated brine,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=4:1→1:3) to give N-Boc compound of thetitle compound as a colorless oil. The obtained oil was dissolved inmethanol (20 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (2mL) was added, and the mixture was stirred at 70° C. for 30 min, andconcentrated under reduced pressure. The residue was suspended in ethylacetate and collected by filtration to give the title compound as acolorless powder (yield 42 mg, 29%).

¹H-NMR (DMSO-d₆) δ: 2.50 (3H, m), 4.00 (2H, t, J=5.8 Hz), 6.71 (1H, d,J=1.8 Hz), 7.44-7.47 (2H, m), 7.55-7.60 (2H, m), 7.73-7.78 (1H, m), 7.89(1H, d, J=1.8 Hz), 8.62 (2H, s), 9.18 (2H, br), 9.23 (1H, s).

Example 230N-Methyl-1-[1-(phenylsulfonyl)-5-(pyridin-3-yl)-1H-pyrrol-3-yl]methanaminedihydrochloride

tert-Butyl{[5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (170mg), pyridin-3-ylboronic acid (244 mg), sodium carbonate (294 mg) andtetrakis(triphenylphosphine)palladium (92 mg) were added to1,2-dimethoxyethane (10 mL) and water (5 mL), and the mixture wasstirred at 90° C. for 4 hr. After the reaction mixture was cooled toroom temperature, water was added and the mixture was extracted withethyl acetate. The extract was washed with water and saturated brine,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluent: hexane-ethyl acetate=1:1→1:3) to give N-Boc compound of thetitle compound as a colorless oil. The obtained oil was dissolved inmethanol (20 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (4mL) was added, and the mixture was stirred at 70° C. for 30 min andconcentrated under reduced pressure. The residue was suspended in amixed solvent of methanol and tetrahydrofuran and collected byfiltration to give the title compound as a colorless powder (yield 77mg, 49%).

¹H-NMR (DMSO-d₆) δ: 2.47 (3H, t, J=5.5 Hz), 3.98 (2H, t, J=5.5 Hz), 6.72(1H, d, J=1.8 Hz), 7.45-7.58 (4H, m), 7.70-7.76 (2H, m), 7.88 (1H, d,J=1.3 Hz), 7.95-7.98 (1H, m), 8.53 (1H, d, J=1.8 Hz), 8.76 (1H, dd,J=1.3, 5.3 Hz), 9.34 (2H, br).

Example 231{1-[5-(2-Fluorophenyl)-2-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminefumarate

A suspension of tert-butyl{1-[5-bromo-2-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate(369 mg), (2-fluorophenyl)boronic acid (234 mg), sodium carbonate (265mg) and tetrakis(triphenylphosphine)palladium (48.9 mg) in1,2-dimethoxyethane (15 mL) and water (7.5 mL) was stirred at 105° C.for 12 hr. After cooling to room temperature, water was added and themixture was extracted with ethyl acetate. The extract was washed withsaturated aqueous sodium hydrogencarbonate solution, water and saturatedbrine, dried over anhydrous magnesium sulfate, filtered, concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent: hexane-ethyl acetate=1:4) to give N-Boc compoundof the title compound. This was dissolved in ethanol (5 mL), and a 4mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added and themixture was stirred at room temperature for 4 hr. The reaction mixturewas concentrated under reduced pressure, and the residue was neutralizedwith saturated aqueous sodium hydrogencarbonate solution (50 mL). Themixture was extracted with ethyl acetate, and the extract was washedwith saturated aqueous sodium hydrogencarbonate solution, water,saturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure. The residue was purified by basicsilica gel column chromatography (eluent: ethyl acetate), and furtherpurified by HPLC (ODS, 0.1% trifluoroacetic acid containing water-0.1%trifluoroacetic acid containing acetonitrile=9:1→0.1% trifluoroaceticacid containing acetonitrile) to give trifluoroacetate of the titlecompound. The obtained trifluoroacetate was neutralized with saturatedaqueous sodium hydrogencarbonate solution, and the mixture was extractedwith ethyl acetate. The extract was washed successively with saturatedaqueous sodium hydrogencarbonate solution, water and saturated brine,dried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure to give a free base of the title compound (yield65 mg). The free base (62 mg) was dissolved in ethyl acetate (2 mL), asolution of fumaric acid (17 mg) in methanol (2 mL) was added, and themixture was stirred for 10 min. The reaction mixture was concentratedunder reduced pressure, and the residue was recrystallized from ethanolto give the title compound as white crystals (yield 25 mg, 7%).

¹H-NMR (DMSO-d₆) δ: 2.35 (3H, s), 2.40 (3H, s), 3.75 (2H, s), 6.46 (3H,s), 7.20-7.28 (3H, s), 7.44-7.52 (1H, m), 7.63-7.67 (1H, m), 7.88-7.92(1H, m), 8.61 (1H, d, J=2.4 Hz), 8.88-8.90 (1H, m), 3H not detected.

Example 2322,2,2-Trifluoro-N-({1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)ethanaminetrifluoroacetate

A solution (15 mL) of2,2,2-trifluoro-N-({1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)acetamide(300 mg) in tetrahydrofuran was cooled at 0° C., 1 mol/L tetrahydrofuransolution of borane (2.84 mL) was added, and the mixture was stirred atroom temperature for 5 hr and then at 50° C. for 3 hr. Water was addedto the reaction mixture, the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluent: hexane-ethylacetate=9:1→2:1), and the obtained oil was purified by preparative HPLC.The purified product was concentrated under reduced pressure, and thecrystals precipitated during the process were collected by filtration.The crystals were recrystallized from ethyl acetate to give the titlecompound as colorless crystals (yield 70 mg, 20%).

¹H-NMR (CDCl₃) δ: 2.35 (3H, s), 3.37 (2H, q, J=7.0 Hz), 4.02 (2H, s),4.80 (2H, br), 6.22 (1H, d, J=1.8 Hz), 7.05-7.40 (9H, m), 7.50 (1H, d,J=1.8 Hz).

The structures of the compounds described in the Examples are shown inTable 25-Table 33.

TABLE 25

Ex. No. R^(1b) R^(2b) R^(3b) R^(4b) R^(5b) addition salt 117

H CH₂NHMe Cl HCl 118

H CH₂NHMe Me HCl 119

H CH₂NHMe H HCl 120

H CH₂NHMe H HCl 121

H CH₂NHMe Me HCl 122

H CH₂NHMe Me HCl 123

H CH₂NHEt Me HCl 124

Me CH₂NHMe Me HCl 125

n-Pr CH₂NHMe Me HCl 126

CH₂NHMe H — 127

H CH₂NHMe Cl HCl 128

H CH₂NHMe F HCl 129

F CH₂NHMe Cl HCl 130

F CH₂NHMe H HCl 131

H CH₂NHMe Me HCl 132

H CH₂NHMe H 2HCl 133

Me CH₂NHMe H HCl 134

Me CH₂NHMe H HClcontinued on Table 26

TABLE 26

Ex. No. R^(1b) R^(2b) R^(3b) R^(4b) R^(5b) addition salt 135

H CH₂NHMe Me 2HCl 136

Cl CH₂NHMe Me HCl 137

n-Bu H CH₂NHMe H HCl 138

H CH₂NHMe H HCl 139

H CH₂NHMe H HCl 140

H CH₂NHMe H HCl 141

H CH₂NHMe H HCl 142

H CH₂NHMe H HCl 143

H CH₂NHMe H HCl 144

H CH₂NHMe H HCl 145/146

H CH₂NHMe H —/HCl 147/148

H CH₂NHMe H —/HCl 149

H CH₂NHMe H HCl 150

H CH₂NHMe H (COOH)₂ 151

H CH₂NHMe H — 152

H CH₂NHMe H HClcontinued on Table 27

TABLE 27

Ex. No. R^(1b) R^(2b) R^(3b) R^(4b) R^(5b) addition salt 153

H CH₂NHMe H HCl 154

H CH₂NHMe H 0.5(COOH)₂ 155

H CH₂NHMe H HCl 156

H CH₂NHMe H 2HCl 157

H CH₂NHMe H HCl 158

H CH₂NHMe H 2HCl 159

H CH₂NHMe H 2HCl 160

H CH₂NHMe H HCl 161

H CH₂NHMe H HCl 162

H CH₂NHMe H HCl 163

H CH₂NHMe H HCl 164

H CH₂NHMe H HCl 165

H CH₂NHMe H HClcontinued on Table 28

TABLE 28

Ex. No. R^(1b) R^(2b) R^(3b) R^(4b) R^(5b) addition salt 166

H CH₂NHMe H

167

H CH₂NHMe H HCl 168

H CH₂NHMe H 2HCl 169

H CH₂NHMe H HCl 170

H CH₂NHMe H (COOH)₂ 171

H CH₂NHMe H 2HCl 172

Me CH₂NHMe H HCl 173

Me CH₂NHMe H HCl 174

Me CH₂NHMe H HCl 175

Me CH₂NHMe H HCl 176

Me CH₂NHMe H HCl 177

Me CH₂NHMe H 2HClcontinued on Table 29

TABLE 29

Ex. No. R^(1b) R^(2b) R^(3b) R^(4b) R^(5b) addition salt 178

Me CH₂NHMe H HCl 179

Me CH₂NHMe H 2HCl 180

Me CH₂NHMe H HCl 181

Me CH₂NHMe H HCl 182

Me CH₂NHMe H CF₃COOH 183

Me CH₂NHMe H HCl 184

H CH₂NHMe Me 0.5(COOH)₂ 185

H CH₂NHMe Me (COOH)₂ 186

Me CH₂NHMe H HCl 187

H CH₂NHMe H HCl 188

H CH₂NHMe H HCl 189

H CH₂NHMe H HClcontinued on Table 30

TABLE 30

Ex. No. R^(1b) R^(2b) R^(3b) R^(4b) R^(5b) addition salt 190

Me CH₂NHMe H HCl 191

Me CH₂NHMe H HCl 192

H CH₂NHMe H — 193

H CH₂NHMe H 2HCl 194

H CH₂NHMe H

195

H CH₂NHMe H HCl 196

H CH₂NHMe H HCl 197

H CH₂NHMe H 2HCl 198

Et CH₂NHMe H HCl 199

i-Pr CH₂NHMe H HCl 200

H CH₂NHMe H HCl 201

H CH₂NHMe H HCl 202

H CH₂NHMe H HClcontinued on Table 31

TABLE 31

Ex. No. R^(1b) R^(2b) R^(3b) R^(4b) R^(5b) addition salt 203

H CH₂NHMe H HCl 204

H CH₂NHMe H HCl 205

H CH₂NHMe H HCl 206

H CH₂NHMe H HCl 207

H CH₂NHMe H — 208

H CH₂NHMe H HCl 209

H CH₂NHMe H HCl 210

H CH₂NHMe H 0.5(COOH)₂ 211

H CH₂NHMe H HCl 212

H CH₂NHMe H 2HCl 213

H CH₂NHMe H HCl 214

H CH₂NHMe H

continued on Table 32

TABLE 32

Ex. No. R^(1b) R^(2b) R^(3b) R^(4b) R^(5b) addition salt 215

H CH₂NHMe H HCl 216

H CH₂NHMe H HCl 217

H CH₂NHMe H 2HCl 218

H CH₂NHMe H HCl 219

H CH₂NHMe H 2HCl 220

H CH₂NHMe H 2HCl 221

H CH₂NHMe H 2HCl 222

H CH₂NHMe H 2HCl 223

H CH₂NHMe H HCl 224

H CH₂NHMe H 2HCl 225

H CH₂NHMe H 2HCl 226

H CH₂NHMe H HCl 227

H CH₂NHMe H 2HClcontinued on Table 33

TABLE 33

Ex. No. R^(1b) R^(2b) R^(3b) R^(4b) R^(5b) addition salt 228

H CH₂NHMe H HCl 229

H CH₂NHMe H HCl 230

H CH₂NHMe H HCl 231

H CH₂NHMe Me

232

H CH₂NHCH₂CF₃ H CF₃COOH

Experimental Example 1 Proton Potassium-Adenosine Triphosphatase(H⁺,K⁺-ATPase) Inhibitory Activity Test

According to the method [Biochem. Biophys. Acta., 728, 31 (1983)] ofWallmark et al., a gastric mucous membrane microsomal fraction wasprepared from the stomach of swine. First, the stomach was removed,washed with tap water, immersed in 3 mol/L brine, and the surface of themucous membrane was wiped with a paper towel. The gastric mucousmembrane was detached, chopped, and homogenized in a 0.25 mol/Lsaccharose solution (pH 6.8) containing 1 mmol/L EDTA and 10 mmol/Ltris-hydrochloric acid using polytron (Kinematica). The obtainedhomogenate was centrifuged at 20,000×g for 30 min and the supernatantwas centrifuged at 100,000×g for 90 min. The precipitate was suspendedin 0.25 mol/L saccharose solution, superimposed on a 0.25 mol/Lsaccharose solution containing 7.5% Ficoll, and centrifuged at 100,000×gfor 5 hr. The fraction containing the interface between the both layerswas recovered, and centrifugally washed with 0.25 mol/L saccharosesolution.

The obtained microsomal fraction was used as a proton,potassium-adenosine triphosphatase standard product.

To 40 μL of a 50 mmol/L HEPES-tris buffer (5 mmol/L magnesium chloride,10 mmol/L potassium chloride, 10 μmol/L valinomycin, pH=6.5) containing2.5 μg/mL (based on the protein concentration) of the enzyme standardproduct was added a test compound (5 μL) dissolved in a 10% aqueousdimethyl sulfoxide solution, and the mixture was incubated at 37° C. for30 min. The enzyme reaction was started by adding 5 μL of a 2 mmol/Ladenosine triphosphate tris salt solution (50 mmol/L HEPES-tris buffer(5 mmol/L magnesium chloride, pH 6.5)). The enzyme reaction was carriedout at 37° C. for 20 min, and 15 μL of a malachite green solution (0.12%malachite green solution in sulfuric acid (2.5 mol/L), 7.5% ammoniummolybdate and 11% Tween 20 were mixed at a ratio of 100:25:2) was addedto quench the reaction. After allowing to stand at room temperature for15 min, the resulting reaction product of inorganic phosphorus withmalachite green was calorimetrically determined at a wavelength of 610nm. In addition, the amount of the inorganic phosphoric acid in thereaction solution free of potassium chloride was measured in the samemanner, which was subtracted from the inorganic phosphoric acid amountin the presence of potassium chloride to determine the proton,potassium-adenosine triphosphatase activity. The inhibitory rate (%) wasdetermined from the activity value of the control and the activityvalues of various concentrations of the test compound, and the 50%inhibitory concentration (IC₅₀) of the proton, potassium-adenosinetriphosphatase was determined. The results are shown in Tables 34 and35.

TABLE 34 Example compound IC₅₀ (μM) 7 0.091 11 0.051 12 0.71

TABLE 35 H⁺/K⁺-ATPase Example No. inhibitory activity (IC₅₀, nM) 30 4.243 51 140 78 152 33 157 13 161 62 165 9.0 166 22 204 86 220 36 225 8.9

From the results of Tables 34 and 35, it is clear that compound (I) ofthe present invention has a superior H⁺/K⁺-ATPase inhibitory activity.

INDUSTRIAL APPLICABILITY

Since compound (I) shows a superior proton pump inhibitory effect, itcan provide a clinically useful pharmaceutical agent for the prophylaxisand/or treatment of peptic ulcer, Zollinger-Ellison syndrome, gastritis,reflux esophagitis, gastroesophageal reflux disease (SymptomaticGastroesophageal Reflux Disease (symptomatic GERD)) free of esophagitis,NUD (Non Ulcer Dyspepsia), gastric cancer, stomach MALT lymphoma, ulcercaused by non-steroidal anti-inflammatory agents or gastric hyperacidityand ulcer due to postoperative stress, and the like; a Helicobacterpylori eradicating agent; an inhibitor of upper gastrointestinalhemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagicgastritis or invasive stress. Since compound (I) shows low toxicity andis superior in water-solubility, in vivo kinetics and efficacyexpression, it is useful as a pharmaceutical. Moreover, since compound(I) is stable even under acidic conditions, which enables oraladministration of the compound as a conventional tablet and the likewithout formulating an enteric-coated preparation. This has aconsequence that the preparation of tablet and the like can be madesmaller, which is advantageous in that it is easily taken by patientshaving difficulty in swallowing, particularly the elderly and children.In addition, since a sustained release effect afforded by enteric-coatedpreparations is absent, expression of a gastric acidsecretion-suppressive action is rapid, and alleviation of symptoms suchas pain and the like is rapid.

This application is based on patent application Nos. 2004-289169 and2005-44740 filed in Japan, the contents of which are incorporated infull herein by this reference.

1-4. (canceled)
 5. A compound represented by the formula (II-a)

wherein X¹ is —SO₂—, —SO₂—N(R⁷)— (wherein R⁷ is a hydrogen atom or anoptionally substituted hydrocarbon group), —N(R⁸)—SO₂— (wherein R⁸ is ahydrogen atom or an optionally substituted hydrocarbon group), —N(R⁹)—(wherein R⁹ is a hydrogen atom or an optionally substituted hydrocarbongroup) or —O—, Y¹ is an optionally substituted alkylene group, R¹⁰ is anoptionally substituted hydrocarbon group or an optionally substitutedheterocyclic group, R¹¹ is a hydrogen atom, an optionally substitutedhydrocarbon group, an optionally substituted thienyl group, anoptionally substituted benzo[b]thienyl group, an optionally substitutedfuryl group, an optionally substituted pyridyl group, an optionallysubstituted pyrazolyl group or an optionally substituted pyrimidinylgroup, R¹² and R¹³ are each independently a hydrogen atom, an optionallysubstituted hydrocarbon group, an acyl group, a halogen atom, a cyanogroup or a nitro group (provided that R¹² and R¹³ are not simultaneouslyhydrogen atoms), and R¹⁴ and R¹⁵ are each independently a hydrogen atomor an optionally substituted hydrocarbon group, with the proviso that3-[[2,3-dimethyl-1-(4-methylphenyl)sulfonyl]-1H-pyrrol-4-yl]-2-methyl-alaninemethyl ester is excluded, or a salt thereof.
 6. A compound representedby the formula (II-b)

wherein X² is a —SO₂—N(R⁷)— (wherein R⁷ is a hydrogen atom or anoptionally substituted hydrocarbon group), —N(R⁸)—SO₂— (wherein R⁸ is ahydrogen atom or an optionally substituted hydrocarbon group), —N(R⁹)—(wherein R⁹ is a hydrogen atom or an optionally substituted hydrocarbongroup) or —O—, Y² is an optionally substituted alkylene group, R¹⁶ is anoptionally substituted hydrocarbon group or an optionally substitutedheterocyclic group, R¹⁷ is a hydrogen atom, an optionally substitutedhydrocarbon group, an optionally substituted thienyl group, anoptionally substituted benzo[b]thienyl group, an optionally substitutedfuryl group, an optionally substituted pyridyl group, an optionallysubstituted pyrazolyl group or an optionally substituted pyrimidinylgroup, R¹⁸ and R¹⁹ are each a hydrogen atom, and R²⁰ and R²¹ are eachindependently a hydrogen atom or an optionally substituted hydrocarbongroup, provided that R¹⁷ should not be a 1,3-dioxaindan-6-yl group, or asalt thereof.
 7. (canceled)
 8. (canceled)
 9. A prodrug of the compoundof claim 5 or claim
 6. 10. A pharmaceutical agent comprising thecompound of claim 5 or claim
 6. 11. The pharmaceutical agent of claim10, which is an agent for the prophylaxis or treatment of peptic ulcer,Zollinger-Ellison syndrome, gastritis, reflux esophagitis,gastroesophageal reflux disease (Symptomatic Gastroesophageal RefluxDisease (symptomatic GERD)) free of esophagitis, NUD (Non UlcerDyspepsia), gastric cancer, stomach MALT lymphoma, ulcer caused by anon-steroidal anti-inflammatory agent or gastric hyperacidity and ulcerdue to postoperative stress; or an inhibitor of upper gastrointestinalhemorrhage due to peptic ulcer, acute stress ulcer, hemorrhagicgastritis or invasive stress.
 12. A method for the prophylaxis ortreatment of peptic ulcer, Zollinger-Ellison syndrome, gastritis, refluxesophagitis, gastroesophageal reflux disease (SymptomaticGastroesophageal Reflux Disease (symptomatic GERD)) free of esophagitis,NUD (Non Ulcer Dyspepsia), gastric cancer, stomach MALT lymphoma, ulcercaused by a non-steroidal anti-inflammatory agent or gastrichyperacidity and ulcer due to postoperative stress; or a method ofinhibiting upper gastrointestinal hemorrhage due to peptic ulcer, acutestress ulcer, hemorrhagic gastritis or invasive stress, which comprisesadministering an effective amount of the compound of claim 5 or claim 6or a prodrug thereof to a mammal.
 13. (canceled)
 14. A method for acidsecretion inhibition, which comprises administering an effective amountof a compound of formula (I)

wherein X and Y are the same or different and each is a bond or a spacerhaving 1 to 20 atoms in the main chain, R¹ is an optionally substitutedhydrocarbon group or an optionally substituted heterocyclic group, R²,R³ and R⁴ are the same or different and each is a hydrogen atom, anoptionally substituted hydrocarbon group, an optionally substitutedthienyl group, an optionally substituted benzo[b]thienyl group, anoptionally substituted furyl group, an optionally substituted pyridylgroup, an optionally substituted pyrazolyl group, an optionallysubstituted pyrimidinyl group, an acyl group, a halogen atom, a cyanogroup or a nitro group, and R⁵ and R⁶ are the same or different and eachis a hydrogen atom or an optionally substituted hydrocarbon group, or asalt thereof, or a prodrug thereof, to a mammal.
 15. The method of claim14, wherein X is —SO₂—, —SO₂—N(R⁷)— (wherein R⁷ is a hydrogen atom or anoptionally substituted hydrocarbon group), —N(R⁸)—SO₂— (wherein R⁸ is ahydrogen atom or an optionally substituted hydrocarbon group), —N(R⁹)—(wherein R⁹ is a hydrogen atom or an optionally substituted hydrocarbongroup) or —O—.
 16. The method of claim 14, wherein X is —SO₂—.
 17. Amethod for the prophylaxis or treatment of peptic ulcer,Zollinger-Ellison syndrome, gastritis, reflux esophagitis,gastroesophageal reflux disease (Symptomatic Gastroesophageal RefluxDisease (symptomatic GERD)) free of esophagitis, NUD (Non UlcerDyspepsia), gastric cancer, stomach MALT lymphoma, ulcer caused by anon-steroidal anti-inflammatory agent or gastric hyperacidity and ulcerdue to postoperative stress; or a method of inhibiting uppergastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer,hemorrhagic gastritis or invasive stress, which comprises administeringan effective amount of a compound of formula (I)

wherein X and Y are the same or different and each is a bond or a spacerhaving 1 to 20 atoms in the main chain, R¹ is an optionally substitutedhydrocarbon group or an optionally substituted heterocyclic group, R²,R³ and R⁴ are the same or different and each is a hydrogen atom, anoptionally substituted hydrocarbon group, an optionally substitutedthienyl group, an optionally substituted benzo[b]thienyl group, anoptionally substituted furyl group, an optionally substituted pyridylgroup, an optionally substituted pyrazolyl group, an optionallysubstituted pyrimidinyl group, an acyl group, a halogen atom, a cyanogroup or a nitro group, and R⁵ and R⁶ are the same or different and eachis a hydrogen atom or an optionally substituted hydrocarbon group, or asalt thereof, or a prodrug thereof, to a mammal.
 18. A method for protonpump inhibition, which comprises administering an effective amount of acompound of formula (I)

wherein X and Y are the same or different and each is a bond or a spacerhaving 1 to 20 atoms in the main chain, R¹ is an optionally substitutedhydrocarbon group or an optionally substituted heterocyclic group, R²,R³ and R⁴ are the same or different and each is a hydrogen atom, anoptionally substituted hydrocarbon group, an optionally substitutedthienyl group, an optionally substituted benzo[b]thienyl group, anoptionally substituted furyl group, an optionally substituted pyridylgroup, an optionally substituted pyrazolyl group, an optionallysubstituted pyrimidinyl group, an acyl group, a halogen atom, a cyanogroup or a nitro group, and R⁵ and R⁶ are the same or different and eachis a hydrogen atom or an optionally substituted hydrocarbon group, or asalt thereof, or a prodrug thereof, to a mammal.
 19. The method of claim18, wherein X is —SO₂—, —SO₂—N(R⁷)— (wherein R⁷ is a hydrogen atom or anoptionally substituted hydrocarbon group), —N(R⁸)—SO₂— (wherein R⁸ is ahydrogen atom or an optionally substituted hydrocarbon group), —N(R⁹)—(wherein R⁹ is a hydrogen atom or an optionally substituted hydrocarbongroup) or —O—.
 20. The method of claim 18, wherein X is —SO₂—.
 21. Amethod for the prophylaxis or treatment of peptic ulcer,Zollinger-Ellison syndrome, gastritis, reflux esophagitis,gastroesophageal reflux disease (Symptomatic Gastroesophageal RefluxDisease (symptomatic GERD)) free of esophagitis, NUD (Non UlcerDyspepsia), gastric cancer, stomach MALT lymphoma, ulcer caused by anon-steroidal anti-inflammatory agent or gastric hyperacidity and ulcerdue to postoperative stress; or a method of inhibiting uppergastrointestinal hemorrhage due to peptic ulcer, acute stress ulcer,hemorrhagic gastritis or invasive stress, which comprises administeringan effective amount of a compound of formula (I)

wherein X and Y are the same or different and each is a bond or a spacerhaving 1 to 20 atoms in the main chain, R¹ is an optionally substitutedhydrocarbon group or an optionally substituted heterocyclic group, R²,R³ and R⁴ are the same or different and each is a hydrogen atom, anoptionally substituted hydrocarbon group, an optionally substitutedthienyl group, an optionally substituted benzo[b]thienyl group, anoptionally substituted furyl group, an optionally substituted pyridylgroup, an optionally substituted pyrazolyl group, an optionallysubstituted pyrimidinyl group, an acyl group, a halogen atom, a cyanogroup or a nitro group, and R⁵ and R⁶ are the same or different and eachis a hydrogen atom or an optionally substituted hydrocarbon group, or asalt thereof, or a prodrug thereof, to a mammal.